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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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(Disulfide bridge: 23-39)
ChemSpider 2D Image | vosoritide | C176H290N56O51S3
SVG Image




L-prolyl-glycyl-L-glutaminyl-L-alpha-glutamyl-L-histidyl-L-prolyl-L-asparagyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysyl-glycyl-L-alanyl-L-asparagyl-L-lysyl-L-lysyl-glycyl-L-leucyl-L-seryl-L-lysyl-glycyl-L-cysteinyl-L-phenylalanyl-glycyl-L-leucyl-L-lysyl-L-leucyl-L-alpha-aspartyl-L-arginyl-L-isoleucyl-glycyl-L-seryl-L-methionyl-L-seryl-glycyl-L-leucyl-glycyl-L-cysteine (23->39)-disulfide

(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-16,22-bis(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid


Formula C176H290N56O51S3
CAS 1480724-61-5
Mol weight 4102.7254

1480724-61-5[RN]BMN 111L-Cysteine, L-prolylglycyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-, cyclic (23→39)-disulfideL-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfideUNII:7SE5582Q2Pвосоритид [Russian] [INN]فوسوريتيد [Arabic] [INN]伏索利肽 [Chinese] [INN]

Voxzogo, 2021/8/26 EU APPROVED

Product details
Name Voxzogo
Agency product number EMEA/H/C/005475
Active substance Vosoritide
International non-proprietary name (INN) or common name vosoritide
Therapeutic area (MeSH) Achondroplasia
Anatomical therapeutic chemical (ATC) code M05BX
OrphanOrphan This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.
Publication details
Marketing-authorisation holder BioMarin International Limited
Date of issue of marketing authorisation valid throughout the European Union 26/08/2021

On 24 January 2013, orphan designation (EU/3/12/1094) was granted by the European Commission to BioMarin Europe Ltd, United Kingdom, for modified recombinant human C-type natriuretic peptide for the treatment of achondroplasia.

The sponsorship was transferred to BioMarin International Limited, Ireland, in February 2019.

This medicine is now known as Vosoritide.

The medicinal product has been authorised in the EU as Voxzogo since 26 August 2021.


Treatment of Achondroplasia
modified recombinant human C-type natriuretic peptide (CNP)

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.[1]

The most common side effects include injection site reactions (such as swelling, redness, itching or pain), vomiting and decreased blood pressure.[1]

Vosoritide was approved for medical use in the European Union in August 2021.[1][2]

Voxzogo is a medicine for treating achondroplasia in patients aged 2 years and older whose bones are still growing.

Achondroplasia is an inherited disease caused by a mutation (change) in a gene called fibroblast growth-factor receptor 3 (FGFR3). The mutation affects growth of almost all bones in the body including the skull, spine, arms and legs resulting in very short stature with a characteristic appearance.

Achondroplasia is rare, and Voxzogo was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 24 January 2013. Further information on the orphan designation can be found here:

Voxzogo contains the active substance vosoritide.

Achondroplasia Posters | Fine Art America

Medical uses

Vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.[1]

Mechanism of action

AChondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.[3]

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3).[1] FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.[3]

The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life,[3] allowing for once-daily administration.[4]



Vosoritide is an analogue of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence isPGQEHPNARKYKGANKKGLS KGCFGLKLDIGSMSGLGC

with a disulfide bridge between positions 23 and 39 (underlined).[5] The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.


Vosoritide is being developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, has orphan drug status in the US as well as the European Union.[1][2][6] As of September 2015, it is in Phase II clinical trials.[7][4]

Society and culture


Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritide’s study results by saying that dwarfism is not a disease and consequently does not need treatment.[8]


Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01).[9] The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.[7][10]

As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights,[10] or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.[4]


  1. Jump up to:a b c d e f g “Voxzogo EPAR”European Medicines Agency. 23 June 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. Jump up to:a b “European Commission Approves BioMarin’s Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close”BioMarin Pharmaceutical Inc. (Press release). 27 August 2021. Retrieved 9 September 2021.
  3. Jump up to:a b c Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). “Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia”American Journal of Human Genetics91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014PMC 3516592PMID 23200862.
  4. Jump up to:a b c Clinical trial number NCT02055157 for “A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)” at
  5. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN): List 112” (PDF). WHO Drug Information28 (4): 539. 2014.
  6. ^ “Food and Drug Administration Accepts BioMarin’s New Drug Application for Vosoritide to Treat Children with Achondroplasia” (Press release). BioMarin Pharmaceutical. 2 November 2020. Retrieved 9 September 2021 – via PR Newswire.
  7. Jump up to:a b Spreitzer H (6 July 2015). “Neue Wirkstoffe – Vosoritid”. Österreichische Apothekerzeitung (in German) (14/2015): 28.
  8. ^ Pollack A (17 June 2015). “Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says”The New York Times.
  9. ^ “BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study”. BioMarin. 17 June 2015.
  10. Jump up to:a b “Vosoritid” (in German). 20 June 2015.

External links

  • “Vosoritide”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade names Voxzogo
Other names BMN-111
Routes of
Subcutaneous injection
ATC code None
Legal status
Legal status EU: Rx-only [1]
CAS Number 1480724-61-5
DrugBank DB11928
ChemSpider 44210446
KEGG D11190
Chemical and physical data
Formula C176H290N56O51S3
Molar mass 4102.78 g·mol−1
3D model (JSmol) Interactive image

/////////Vosoritide, Voxzogo, PEPTIDE, ボソリチド (遺伝子組換え) , восоритид , فوسوريتيد , 伏索利肽 , APPROVALS 2021, EU 2021, BMN 111, ORPHAN DRUG



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Saquinavir structure.svg


Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852



(-)-cis-N-tert-butyldecahydro-2-{(2R,3S)-2-hydroxy-4-phenyl-3-{[N-(2-quinolylcarbonyl)-L-asparaginyl]amino}butyl}-(3S,4aS,8aS)-isoquinoline-3 carboxamide monomethanesulfonate

Product Ingredients

Saquinavir mesylateUHB9Z3841A149845-06-7IRHXGOXEBNJUSN-YOXDLBRISA-N

CAS Registry Number: 127779-20-8 
CAS Name: (2S)-N1[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide 
Additional Names: (S)-N-[(aS)-a-[(1R)-2-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(1H)-isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamido succinamide; N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl](4aS,8aS)-isoquinoline-3(S)-carboxamide 
Manufacturers’ Codes: Ro-31-8959Molecular Formula: C38H50N6O5Molecular Weight: 670.84Percent Composition: C 68.04%, H 7.51%, N 12.53%, O 11.92% 
Literature References: Selective HIV protease inhibitor.Prepn: J. A. Martin, S. Redshaw, EP432695eidem,US5196438 (1991, 1993 both to Hoffmann-LaRoche); K. E. B. Parkes et al.,J. Org. Chem.59, 3656 (1994).In vitro HIV proteinase inhibition: N. A. Roberts et al.,Science248, 358 (1990). Antiviral properties: J. C. Craig et al.,Antiviral Res.16, 295 (1991); S. Galpin et al.,Antiviral Chem. Chemother.5, 43-45 (1994).Clinical evaluation of tolerability and activity: V. S. Kitchen et al.,Lancet345, 952 (1995). Review of pharmacology and clinical experience: S. Kravcik, Expert Opin. Pharmacother.2 303-315 (2001). 
Properties: White crystalline solid. [a]D20 -55.9° (c = 0.5 in methanol). Soly (21°): 0.22 g/100 ml water.Optical Rotation: [a]D20 -55.9° (c = 0.5 in methanol) 
Derivative Type: Methanesulfonate saltCAS Registry Number: 149845-06-7Additional Names: Saquinavir mesylateManufacturers’ Codes: Ro-31-8959/003Trademarks: Fortovase (Roche); Invirase (Roche)Molecular Formula: C38H50N6O5.CH3SO3HMolecular Weight: 766.95Percent Composition: C 61.08%, H 7.10%, N 10.96%, O 16.69%, S 4.18% 
Therap-Cat: Antiviral.Keywords: Antiviral; Peptidomimetics; HIV Protease Inhibitor.

Saquinavir mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 6, 1995, then approved by European Medicine Agency (EMA) on Oct 4, 1996, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Sep 5, 1997. It was developed by Roche, then marketed as Invirase® by Roche in the US and EU and by Chugai in JP.

Saquinavir mesylate is an inhibitor of HIV-1 protease. It is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of HIV-1 protease that required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. It is indicated for the treatment of HIV-1 infection in combination with ritonavir and other antiretroviral agents in adults (over the age of 16 years).

Invirase® is available as capsule for oral use, containing 200 mg of free Saquinavir. The recommended dose is 1000 mg twice daily in combination with ritonavir 100 mg twice daily for adults.

Human medicines European public assessment report (EPAR): Invirase, saquinavir, HIV Infections, 03/10/1996, 47, Authorised (updated)

EU 08/09/2021

Invirase is an antiviral medicine used to treat adults infected with the human immunodeficiency virus type 1 (HIV 1), a virus that causes acquired immune deficiency syndrome (AIDS). Invirase should only be used in combination with ritonavir (another antiviral medicine) and other antiviral medicines.

Invirase contains the active substance saquinavir.

Product details
Agency product numberEMEA/H/C/000113
Active substancesaquinavir
International non-proprietary name (INN) or common namesaquinavir
Therapeutic area (MeSH)HIV Infections
Anatomical therapeutic chemical (ATC) codeJ05AE01
Publication details
Marketing-authorisation holderRoche Registration GmbH
Date of issue of marketing authorisation valid throughout the European Union03/10/1996

Invirase can only be obtained with a prescription and treatment should be started by a doctor who has experience in the treatment of HIV infection.

Invirase is available as capsules (200 mg) and tablets (500 mg). For patients already taking HIV medicines, the recommended dose of Invirase is 1,000 mg with 100 mg ritonavir twice daily. For patients who are not taking HIV medicines, Invirase is started at 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment, given in combination with other HIV medicines. After 7 days, the recommended dose of Invirase is 1,000 mg twice daily with ritonavir 100 mg twice daily in combination with other HIV medicines.

For more information about using Invirase, see the package leaflet or contact a doctor or pharmacist.

The active substance in Invirase, saquinavir, is a ‘protease inhibitor’. It blocks protease, an enzyme involved in the reproduction of HIV. When the enzyme is blocked, the virus does not reproduce normally, slowing down the spread of infection. Ritonavir is another protease inhibitor that is used as a ‘booster’. It slows the breakdown of saquinavir, increasing the levels of saquinavir in the blood. This allows effective treatment while avoiding a higher dose of saquinavir. Invirase, taken in combination with other HIV medicines, reduces the viral load (the amount of HIV in the blood) and keeps it at a low level. Invirase does not cure HIV infection or AIDS, but it may hold off the damage to the immune system and the development of infections and diseases associated with AIDS.

Invirase received a marketing authorisation valid throughout the EU on 4 October 1996.

Drug Name:Saquinavir MesylateResearch Code:Ro-31-8959; Sch-52852Trade Name:Invirase®MOA:HIV-1 protease inhibitorIndication:HIV infectionStatus:ApprovedCompany:Roche (Originator) , ChugaiSales:ATC Code:J05AE01

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2004-12-17New dosage formInviraseHIV infectionTabletEq. 500 mg SaquinavirRochePriority
1995-12-06First approvalInviraseHIV infectionCapsuleEq. 200 mg SaquinavirRochePriority


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1996-10-04First approvalInviraseHIV infectionCapsule200 mgRoche 
1996-10-04First approvalInviraseHIV infectionTablet, Film coated500 mgRoche 


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-09-01New dosage formInviraseHIV infectionTablet500 mgChugai 
1997-09-05First approvalInviraseHIV infectionCapsule200 mgChugai 


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2014-03-13Marketing approval因服雷/InviraseHIV infectionTabletEq. 500 mg SaquinavirRoche 
2009-07-01Marketing approval因服雷/InviraseHIV infectionCapsuleEq. 200 mg SaquinavirRoche

Route 1

Reference:1. US5196438A.Route 2

Reference:1. J. Org. Chem199459, 3656-3664.Route 3

Reference:1. WO2006134612A1.


English: DOI: 10.1021/jo00393a034

DOI: 10.1021/jo00092a026

DOI: 10.1016/S0040-4039(00)77633-7

File:Saquinavir synthesis.png


In the following, a possible route for the synthesis of Saquinavir is presented. Since Diazomethane is used, the synthesis is not suitable for a scaled up process. Roche has solved this problem with another reaction mechanism. The mechanism for laboratories starts with a ring opening substitution of an epoxid derivative of Phenylalanine with decaisohydroquinoline in dry iso-propanol with nitrogen atmosphere. The intermediate is purified by flash chromatography. In the second step of synthesis, the protection group is removed with gaseous hydrogen and a carbon/palladium catalyst. Furthermore, the new product reacts with N-Benzyloxycarbonyl-Lasparagine(Cbz AsnOH) in the solvents Cbz Asparagine L(Cbz Asn L) and 1- Hydroxybenzotriazolehydrat(HBOT). Afterwards, the protecting group of the former Asparagine is removed with another mixture of gaseous hydrogen and carbon/palladium catalyst. The final intermediate gets stirred in the last step of synthesis together with the solvents Tetrahydrofuran, HBOT and DCC. The mechanism formulated in detail can be found in the Appendix (VIII).7

Kevin E. B. Parkes; David J. Bushnell; et al. Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656–3664.



he synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.


J Org Chem 1994,59(13),3656

Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.


2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.


3) The condensation of N-(tert-butoxycarbonyl)-L-phenylalaninal (XXV) with 2-(trimethylsilyl)thiazole (XXVI) by means of tetrabutylammonium fluoride gives the thiazole derivative (XXVII), which is cleaved by reaction with methyl iodide (formation of the thiazolium derivative) and treated with NaBH4 and HgCl2 to afford the protected 3(S)-amino-2(S)-hydroxy-4-phenylbutanal (XXVIII). Finally, this compound is reductocondensed with isoquinoline (XI) by means of sodium cyanoborohydride to yield the protected condensation product (XII), already obtained in scheme 16810301a.


4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.


The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III), which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V), which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI). Finally, this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).


J Label Compd Radiopharm 1998,41(12),1103

[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III), which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV). The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V), which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.


Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII), which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX). The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X), which is brominated with Br2 as before giving the tribromo derivative (XI). The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII), which is finally condensed with Ro-32-0445 (VI) as before.


Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII), which is brominated as described yielding the tribromo derivative (XIV). The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV), which is finally condensed with Ro-32-0445 (VI) as indicated.


Tritiated saquinavir: The cyclization of 4-bromoaniline (XVI) with crotonic aldehyde (II) by means of ZnCl2/HCl gives 6-bromo-4-methylquinoline (XVII), which is brominated as before giving tetrabromo derivative (XVIII). The hydrolysis of (XVIII) with sulfuric cid affords 6-bromoquinoline-2-carboxylic acid (XIX), which is condensed with Ro-32-0445 (VI) by means of HOBT and DCC as indicated giving the bromo derivative of saquinavir (XX). Finally, this compound is tritiated with T2 over Pd/C in ethanol.


5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII), which is reduced with Sn/HCl to the aniline (XXIII). The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV), which is brominated as before givig the tribromo derivative (XXV). The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI), which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.

Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3] It is taken by mouth.[3]

Common side effects include nausea, vomiting, diarrhea, and feeling tired.[3] More serious side effects include problems with QT prolongationheart blockhigh blood lipids, and liver problems.[3] It appears to be safe in pregnancy.[3] It is in the protease inhibitor class and works by blocking the HIV protease.[3]

Saquinavir was patented in 1988 and first sold in 1995.[4][5]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3]

Side effects

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhoeanausea, loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.[medical citation needed]

Bioavailability and drug interactions

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.[6]

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.[medical citation needed]

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.[medical citation needed]

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.[7]

Mechanism of action

Saquinavir is a protease inhibitorProteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.[8]


New HIV infections and deaths, before and after the FDA approval of “highly active antiretroviral therapy”,[9] of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors.Cully, Megan (28 November 2018). “Protease inhibitors give wings to combination therapy”nature. Open Publishing. Retrieved 28 October 2020. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.}}[9]

Saquinavir was developed by the pharmaceutical company Roche.[10] Saquinavir was the sixth antiretroviral and the first protease inhibitor approved by the US Food and Drug Administration (FDA), leading ritonavir and indinavir by a few months.[11] This new class of antiretrovirals played a critical role in the development of highly active antiretroviral therapy (HAART), which helped significantly lower the risk of death from AIDS-related causes, as seen by a reduction of the annual U.S. HIV-associated death rate, from over 50,000 to about 18,000 over a period of two years.[9][12]

Roche requested and received approval of Invirase via the FDA’s “Accelerated Approval” program—a process designed to speed drugs to market for the treatment of serious diseases—a decision that was controversial, as AIDS activists disagreed over the benefits of thorough testing versus early access to new drugs.[13][better source needed] It was approved again on November 7, 1997, as Fortovase,[14] a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, given reduced demand, Fortovase would cease being marketed early in 2006, in favor of Invirase boosted with ritonavir,[15] owing to the ability of the latter co-formulated drug to inhibit the enzyme that metabolizes the AIDS drugs.[citation needed]

Society and culture


As of 2015, it is not available as a generic medication.[16]


Two formulations have been marketed:

  • a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
  • a soft-gel capsule formulation of saquinavir (microemulsion,[17] orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.[18]


  1. ^ “Saquinavir Use During Pregnancy” 20 March 2018. Retrieved 28 January 2020.
  2. ^ “Invirase- saquinavir mesylate capsule INVIRASE- saquinavir mesylate tablet, film coated”DailyMed. 26 December 2019. Retrieved 28 January 2020.
  3. Jump up to:a b c d e f g h i “Saquinavir”. The American Society of Health-System Pharmacists. Archived from the original on 8 September 2015. Retrieved 5 September 2015.
  4. ^ Minor, Lisa K. (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN 9781420015706Archived from the original on 31 March 2016.
  5. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN 9783527607495.
  6. ^ “Fortovase” 22 March 2019. Retrieved 28 January2020.
  7. ^ Winston A, Back D, Fletcher C, et al. (2006). “Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers”. AIDS20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8aPMID 16791014S2CID 44506039.
  8. ^ Raphael Dolin, Henry Masur, Michael S. Saag. “AIDS Therapy“, Churchill Livingstone, (1999), p. 129.
  9. Jump up to:a b c “HIV Surveillance—United States, 1981-2008”Archivedfrom the original on 9 November 2013. Retrieved 8 November 2013.
  10. ^ J. Hilts, Philip (8 December 1995). “MF.D.A. Backs A New Drug To Fight AIDS”New York Times. Retrieved 28 October 2020.
  11. ^ “Antiretroviral Drug Discovery and Development”NIH. 26 November 2018. Retrieved 29 October 2020.
  12. ^ The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to “highly active antiretroviral therapy”, without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
  13. ^ “Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications”. The Body. Archived from the original on 9 November 2013. Retrieved 20 February 2013.
  14. ^ “Drug Approval Package: Fortovase/Saquinavir NDA 20828”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 28 January 2020.
  15. ^ Withdrawal of Fortovase (PDF) Archived 2006-05-14 at the Wayback Machine
  16. ^ “Generic Invirase Availability” Retrieved 9 July2020.
  17. ^ Gibaud S, Attivi D (August 2012). “Microemulsions for oral administration and their therapeutic applications” (PDF). Expert Opinion on Drug Delivery9 (8): 937–51. doi:10.1517/17425247.2012.694865PMID 22663249S2CID 28468973.
  18. ^ News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir) Archived 2015-02-22 at the Wayback Machine

External links


Clinical data
Trade namesInvirase, Fortovase
License dataEU EMAby INNUS DailyMedSaquinavir
AU: B1[1]
ATC codeJ05AE01 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Bioavailability~4% (without ritonavir boosting)[2]
Protein binding98%
MetabolismLiver, mainly by CYP3A4
Elimination half-life9–15 hours
Excretionfeces (81%) and urine (3%)
showIUPAC name
CAS Number127779-20-8 
PubChem CID441243
NIAID ChemDB000640
CompTox Dashboard (EPA)DTXSID6044012 
Chemical and physical data
Molar mass670.855 g·mol−1
3D model (JSmol)Interactive image

///////////////saquinavir, Antiviral, Peptidomimetics, HIV Protease Inhibitor,  Ro-31-8959, EU 2021, APPROVALS 2021, Invirase, Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852







Heavy chain)
(Light chain)
(Disulfide bridge: H22-H96, H152-H208, H228-L214, H234-H’234, H237-H’237, H269-H329, H375-H433, H’22-H’96, H’152-H’208, H’228-L’214, H’269-H’329, H’375-H’433, L23-L88, L134-L194, L’23-L’88, L’134-L’194)


ビメキズマブ (遺伝子組換え)

UCB 4940

Mol weight147227.7921

EU APPROVED, 2021/8/20, Bimzelx

Immunoglobulin G1, anti-​(human interleukin 17A​/interleukin 17F) (human-​Rattus norvegicus monoclonal UCB4940 heavy chain)​, disulfide with human-​Rattus norvegicus monoclonal UCB4940 light chain, dimer

Protein Sequence

Sequence Length: 1338, 455, 455, 214, 214multichain; modified (modifications unspecified)

Product details
Agency product numberEMEA/H/C/005316
Active substanceBimekizumab
International non-proprietary name (INN) or common namebimekizumab
Therapeutic area (MeSH)Psoriasis
Anatomical therapeutic chemical (ATC) codeL04AC

Bimzelx 160 mg solution for injection in pre-filled syringe Bimzelx 160 mg solution for injection in pre-filled pen

The active substance in Bimzelx, bimekizumab, is a monoclonal antibody, a protein designed to attach to interleukins IL-17A, IL-17F and IL-17AF, which are messenger molecules in the body’s immune system (the body’s natural defences). High levels of these interleukins have been shown to be involved in developing inflammatory diseases caused by the immune system, such as plaque psoriasis. By attaching to these interleukins, bimekizumab prevents them from interacting with their receptors (targets) on the surface of the epidermis (outer layer of the skin), which reduces inflammation and improves the symptoms related to plaque psoriasis.,,,

Antipsoriatic, Anti-IL-17A/IL-17F antibody, Monoclonal antibody
Treatment of moderate to severe plaque psoriasis

Bimekizumab, sold under the brand name Bimzelx, is a humanized anti-IL17A, anti-IL-17F, and anti-IL17AF monoclonal antibody[1][2] that is used to treat plaque psoriasis.[1]

The most common side effects include upper respiratory tract infections (nose and throat infection) and oral candidiasis (thrush, a fungal infection in the mouth or throat).[1]

Bimekizumab was approved for medical use in the European Union in August 2021.[1][3]

Drug: bimekizumab
Company: UCB
Used for: psoriasis
Est. 2026 sales: $1.63 billion

Monoclonal antibody treatments for psoriasis are stacking up—but UCB hopes to muscle into the market with bimekizumab this year. The anti-IL-17A and IL-17F injection showed up both Johnson & Johnson’s Stelara and Novartis blockbuster Cosentyx in trials.

UCB’s Stelara head-to-head, the Be Vivid study presented in June at the American Academy of Dermatology and later published in The Lancet,  found 85% of bimekizumab patients had a 90% or greater reduction in the area and severity of their psoriasis symptoms at 16 weeks. Complete skin clearance, indicated by a score of PASI 100, happened in 59% of patients.

Stelara, for its part, helped just half of patients reach PASI 90 and 21% achieve complete skin clearance over the same time period.

That Be Vivid readout raised expectations of a potentially favorable outcome in UCB’s head-to-head study with Novartis blockbuster Cosentyx (secukinumab), called Be Radiant.

RELATED: UCB’s bimekizumab blows J&J’s Stelara away in phase 3, raising expectations for Cosentyx showdown

In July, UCB announced that in that phase 3 study, its candidate had “demonstrate(d) superiority to secukinumab for complete skin clearance at both weeks 16 and 48.” The full study results will be presented “in due course,” UCB promised.

The data from the Cosentyx trial could be worth a lot to UCB, Evaluate wrote in June, adding that Jefferies analysts at the time expected annual sales of bimekizumab to top out around $1.5 billion. If bimekizumab beats Cosentyx, the sales forecast could rise to above $2 billion, it said at the time.

Without specific Cosentyx-topping data from the Be Radiant study in hand, Evaluate pegs consensus sales estimates at $1.63 billion in 2026.

One concern for UCB is whether the smaller pharma will be able to compete with the big marketing budgets in psoriasis. AbbVie’s Skyrizi and Humira, Novartis’ Cosentyx, Eli Lilly’s Taltz and Amgen’s Otezla are just a handful of the psoriasis drugs that have spent millions on mainstream TV ads to build brand names.

RELATED: DiCE scores $80M to roll oral IL-17 psoriasis med into the clinic

In September, the FDA and EMA accepted UCB’s biologics license application (BLA) for bimekizumab for adults with moderate to severe plaque psoriasis, the company reported. Ongoing phase 3 trials are evaluating the drug to treat a variety of other conditions, including psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa.

In the meantime, more competition is on the way. South San Francisco biotech DiCE Molecules, for its part, last month nabbed new funding to the tune of $80 million to roll its oral small molecule IL-17 program into a clinical trial in psoriasis and build out preclinical programs.

In addition to IL-17 rivals, others are also looking to get in on the action—particularly, several TYK2 inhibitors. Bristol Myers Squibb’s deucravacitinib recently bested Otezla in a study, while both Pfizer and Nimbus Therapeutics are in phase 2 studies with prospects of their own.

Psoriatic arthritis (PsA) is a complex and heterogeneous inflammatory disease that affects 20% to 30% of patients with psoriasis and is associated with substantial disability, impaired quality of life (QoL), and several comorbidities.1–3 It involves diverse clinical domains that extend beyond musculoskeletal manifestations (peripheral and axial arthritis, enthesitis and dactylitis): eg, nails, gut, and eyes, in addition to latent or manifest psoriasis.

Although there is still a huge gap in knowledge on the pathophysiology of PsA, what is known has fortunately turned into new treatment approaches that have improved symptoms and outcomes for PsA patients over the last two decades. Pro-inflammatory cytokines have been recognized as potential treatment targets in inflammatory diseases and have led to the creation of a number of anti-cytokine monoclonal antibodies that have revolutionized its treatment, such as TNFα and IL-12/23 inhibitors.4 More recently, the IL-17 pathway has been shown to play an important role in the pathophysiology of psoriatic disease and its blockage has shown to be clinically beneficial, as demonstrated with IL-17A inhibitors secukinumab and ixekizumab.4 Some patients, however, still do not respond, stop responding over time or suffer from side effects, leading to drug discontinuation, and other times combination strategies are required to control all PsA’s disease domains. Thus, there is still a great need for novel therapeutic options.5

Dual inhibitor antibodies target two different cytokines simultaneously potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have a similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F.

Medical uses

Bimekizumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.[1]


This drug is being developed by Belgian pharmaceutical UCB. Phase III trials have demonstrated that bimekizumab is superior to not only adalimumab[4] but also secukinumab[5] for the treatment of plaque psoriasis.


Bimekizumab is the international nonproprietary name (INN).[6]

The Role of Interleukin (IL)‑17A and IL‑17F in Psoriatic Arthritis

The IL-17 cytokine family comprises six different members (from A to F), of which IL-17A is the most studied. Known to be produced by a wide range of immune cells, IL-17A is involved in the pathophysiology of several inflammatory diseases including spondyloarthritis.6–8

Most non-hematopoietic cells possess IL-17 receptors, including fibroblasts, epithelial cells and synoviocytes,8 but despite this ubiquitous presence, IL-17 seems to have only moderate inflammatory capability per se, rather recruiting and amplifying other pathways, such as IL-6, IL-8, TNF and inflammatory-cell attracting chemokines.6,7,9,10

Still, evidence supporting the centrality of the IL-17 pathway in both PsO and PsA is available from a wide range of data.11 Th17 cells, IL-17 protein and related genes are elevated in both skin, blood and synovial fluid of PsO and PsA patients.11,12 In PsA, increased levels of IL-17+ CD4 and CD813,14, as well as IL-17A+Tγδ cells, have been found in the synovial fluid compared with peripheral blood. Specifically, the levels of IL-17+CD8+ cells in the synovial fluid distinguish PsA from rheumatoid arthritis (RA) and correlate with increased DAS28 scores, C-reactive protein levels, power-doppler findings of activity and prevalence of erosions.13 Inhibition of this pathway is capable of normalizing almost four times more disease-related genes than anti-TNFα treatments.11,15

Within the entire IL-17 family, IL-17F is the most structurally homologous (~50%) to IL-17A8 (Figure 1). They can both be secreted as homodimers (ie IL-17A/A or IL-17F/F) or as heterodimers of IL-17A/IL-17F,9 sharing signaling pathways through the same heterodimeric complex of IL-17 receptors A and C (IL-RA/RC) and biologic function.7–9

Figure 1 Summarized schematic of inhibition of the IL-17 cytokine family. *Not approved for psoriatic arthritis. Notes: Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, BioDrugs, Reis J, Vender R, Torres T. Bimekizumab: the first dual inhibitor of interleukin (IL)-17A and IL-17F for the treatment of psoriatic disease and ankylosing spondylitis, COPYRIGHT 2019.6Abbreviations: IL, interleukin; IL-17RA, IL-17 receptor A; IL-17RB, IL-17 receptor B; IL-17RC, IL-17 receptor C; IL-17RE, IL-17 receptor E.

The role of both IL-17A and F in psoriasis pathogenesis has been previously addressed.6,9,16

In enthesitis, a central pathologic process in PsA, Tγδ cells have recently been described that are capable of producing both IL-17A and IL-17F even independently of IL-23 stimulation.17 IL-17A and F had already been shown to promote osteogenic differentiation in in vitro models of human periosteum activated through the use of Th17 and Tγδ cells or through culture with serum from patients with ankylosing spondylitis,18 a mechanism potentially implied in the development of enthesitis. Importantly, both cytokines seem to be equipotent in this role, unlike in inflammatory processes where IL-17F seems to be less potent.18

Both IL-17A and IL-17F, when synergized with TNF, lead to increased production of pro-inflammatory cytokines, such as IL-8 and IL-6 in synoviocytes of PsA patients.9 IL-17A seems to be the most pro-inflammatory of the two cytokines.9,19 However, despite some inconsistencies in the literature regarding IL-17F detection levels which might be attributable to differences in methodology,19 IL-17F levels have been reported to be 30–50 times higher in some cytokine microenvironments, such as in psoriatic skin lesions of PsA patients20 or the synovium,21 which might dilute differences in relative potency. Additionally, IL-17F seems to be significantly increased in the synovium of PsA compared to osteoarthritis (OA) patients, unlike IL-17A.21 Dual neutralization of both IL-17A and IL-17F (using bimekizumab) resulted in greater downregulation of pro-inflammatory cytokine production than a single blockade in synovial fibroblasts.9,19 Critically, in in vitro models, anti-TNF blockade alone did not reduce the production of IL-8 as much as both IL-17A and F neutralization or even just anti-IL17A alone.9,19 In in vitro models of human periosteum dual blockade of IL-17A and F was also more effective in suppressing osteogenic differentiation than the blockade of either cytokine individually.18

Interestingly, in Tγδ cells, the predominant IL-17 production seems to be the F subtype.18 Also of note is the recent description that the IL-17receptorC (IL-17RC) competes with IL-17RA for IL-17F, IL-17A and IL-17A/F heterodimers,22 suggesting the possibility of IL-17RA-independent signaling pathways (and thus not targeted by brodalumab, an anti-IL17RA monoclonal antibody).


Bimekizumab is a humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. In in vitro models, bimekizumab appears to be as potent as ixekizumab at inhibiting IL-17A (also more potent than secukinumab)8 but, unlike those drugs, also possesses the unique ability to inhibit IL-17F as well, functioning as a dual inhibitor. Unlike brodalumab, an IL-17 receptor A blocker – which targets not only IL-17A and F signaling but also IL-17 C, D and E – bimekizumab spares IL-17E (also known as IL-25), for example, which is believed to have anti-inflammatory properties.6

Bimekizumab demonstrates dose-proportional linear pharmacokinetics, with a half-life ranging from 17 to 26 days, and its distribution is restricted to the extravascular compartment.23 Currently, bimekizumab is in advanced clinical development for psoriasis, but also for psoriatic arthritis, and ankylosing spondylitis (both currently in phase III).

Bimekizumab in PsA – Efficacy

Phase I

The first bimekizumab clinical trial in PsA was a phase Ib randomized, double-blind, placebo-controlled clinical trial that included 53 patients (39 treated with bimekizumab, 14 with placebo) with active psoriatic arthritis who had failed conventional disease-modifying antirheumatic drugs (DMARDs) and/or one biologic DMARD. Patients in the active treatment arm were randomized to four different treatment regimens of varying loading doses (ranging from 80 to 560 mg) and maintenance doses (from 40 to 320 mg) at weeks 0, 3 and 6. Patients were followed for up to 20 weeks.9

Patients treated with bimekizumab had a faster response, compared to placebo. This was first detected at week two, with maximal or near-maximal responses maintained up to week 20, for both arthritis and skin psoriasis. ACR20, 50 and 70 responses were maximal at week 8 (80%), week 12 (57%) and week 16 (37%), respectively. For patients with skin involvement, PASI75 and PASI100 responses at week 8 were 100% and 87%, respectively (Table 1).

Table 1 Results from Published Trials Involving Bimekizumab in Psoriatic Arthritis

Phase II

BE ACTIVE10 was a 48-week multicentric, international, phase 2b dose-ranging, randomized, double-blind placebo-controlled trial to assess the efficacy and safety of bimekizumab. Two hundred and six adult patients (out of 308 screened) with active (tender and swollen count >3) PsA (diagnosed according to CASPAR criteria) were enrolled in 5 treatment arms (placebo, 16 mg, 160 mg with single 320 mg loading dose, 160 mg, 320 mg bimekizumab dose, with SC injections every 4 weeks). Concurrent use of TNF inhibitors was not permitted but conventional DMARDs (if on a stable dose and kept throughout the study), corticosteroids (equal or less 10mg/day) and NSAIDs were allowed. Sixteen-milligram bimekizumab (a much lower dose than other treatment arms) was tested with a programmed re-randomization at week 12 to either 160 or 320 mg dosing (meaning no placebo arm after 12 weeks). All patients received treatment up to week 48.

The primary outcome was ACR50 response at 12 weeks, a much more stringent outcome than used for other IL-17 inhibitors. The prespecified analysis was not possible due to the absence of a statistically significant difference versus placebo for the 320 mg group at week 12. All other outcomes were thus considered exploratory, rendering this a failed primary endpoint with no active comparator group.

At 12 weeks, significant ACR50 responses were present for every bimekizumab group, although lower in both the 16 mg and 320 mg dose group (Table 1 reports average values for all bimekizumab treatment groups). The 160 mg dosing had the greatest ACR and PASI response rates. These were confirmed to be increasing response rates up to week 24 and stability thereafter up to week 48, where the results of both 160 and 320 mg were similar. There were also responses in PASI scores, enthesitis, HAQ-DI and SF-36 across all bimekizumab doses. There was no loss of efficacy by week 48.

At the recent American College of Rheumatology (ACR) congress, additional data on BE ACTIVE were reported. BASDAI scoring was improved on the 93 patients in the treatment arm (160–320 mg bimekizumab) who had a baseline score >4 (mean 6.2 ± 1.42). BASDAI50 response rates were 43% and 56% at week 12 and 48, respectively.24

Regarding patient-reported outcomes (PROs), the Health assessment questionnaire Disability Index (HAQ-DI) and the psoriatic arthritis impact of disease-9 (PsAID-9) questionnaire developed specifically to assess health-related quality of life (QoL) in PsA were used on 206 patients from the BE ACTIVE trial. Rapid improvement was registered by week 12 and this response was sustained up to 48 weeks. Better QoL was associated with the better clinical outcomes reported in that study.25,26

Open-Label Extension Study (OLE)

Results from the 108 weeks of follow-up in the open-label extension study of BE ACTIVE (BE ACTIVE2, NCT03347110) have been recently presented.27,28 All patients who completed all 48 weeks of the BE ACTIVE trial were enrolled and switched to the 160 mg dosing regardless of previous treatment dose regimen. Over 108 weeks (an additional 60 weeks of OLE study over the 48 of the original BE ACTIVE trial) there was a 66.7% and 75.4% ACR 50 and body surface area (BSA) 0% response, respectively. Dactylitis and enthesitis were also significantly improved completely resolving in 65.9% and 77.9% of patients, respectively.27 Regarding week 12 responders, ACR20/50/70 and BSA 0% responses were maintained until week 108 in 80/78/81% and 72%, respectively.27 MDA/VLDA responses and DAPSA remission were maintained by 81/72/76% of Week 12 responders, respectively, to Week 120 (MDA/VLDA), and Week 108 (DAPSA remission).

Bimekizumab in PsA – Safety

Phase I

Over 90% of reported adverse events, in both arms, were mild or moderate. In the treatment arm, two fungal infections (oropharyngeal and vulvovaginal candidiasis) were reported, both treated with oral medication. There was no increased incidence of other infections. There were no deaths or severe adverse events resulting from treatment, and no patient discontinued bimekizumab.9

Phase II

No difference was found in the frequency of adverse events between placebo and treatment arms by week 12 in the BE ACTIVE trial. After reallocation (after week 12) and up to the 48 weeks of the trial 151 (74%) of the total 204 patients who ever received bimekizumab reported some AE (exposure adjusted incidence rate 166.8/100 patient-years). Most AE were mild or moderate (the most frequently reported were nasopharyngitis and upper respiratory tract infections) and there was no direct association with bimekizumab dose.

Nine patients (8 of which received bimekizumab) had serious adverse effects. These included one patient with drug-induced liver injury. Another patient also had severe liver enzyme elevation. Both had been given the 320 mg dosing. From the hepatic point of view, the other 11 patients were noted to have increased liver enzymes (>3x ULN). There was no relation with bimekizumab dose, and most were on DMARDs and one was on TB prophylaxis. At least two serious adverse events were related to infections across the entire study period (28 weeks) – 1 hepatitis E infection, 1 cellulitis (both with the 160 mg dosing). Non-severe Candida infection was reported in 7% of the patients, none led to treatment discontinuation. Other serious AEs reported were melanoma in situ (160 mg), suicidal ideation (160 mg loading dose), and neutropenia (320 mg dosing) (only in one patient each).10 In summary, this safety profile overlaps with those of other anti-IL17 therapies.29

In the OLE study, at week 108, serious adverse events occurred in 9.3% of patients (no deaths or major adverse cardiac events) and a total of 8.8% of patients withdrew from the study due to side effects. Full publication is still pending but the authors share that the safety profile observed in the OLE study reflected previous observations.27


Dual inhibitor antibodies represent a novel therapeutic strategy, and a logical extension of the success monoclonal antibodies has had over the last couple of decades.

Here we review the most recent information on IL-17A and F inhibition in psoriatic arthritis through the first-of-its-class bimekizumab, a dual inhibitor of both cytokines.

The importance of the IL-17 pathway in psoriatic arthritis, already suggested by preclinical data, was reinforced by the excellent results obtained by secukinumab30 or ixekizumab31 in the control of the disease in the last few years.

Indeed, IL-17 seems to be involved in all of the clinical domains of psoriatic arthritis. In preclinical trials, it has been shown that both IL-17A and F are capable of inducing pro-inflammatory cytokines, like IL-8 or IL-6, in synoviocytes, periosteum and the skin,23 and that this activation was greatly suppressed by blocking both these cytokines simultaneously. Research is expanding on the differential role of IL-17F in different environments,18,21 compared with the more studied IL-17A, as well as possible alternative signaling pathways.22 Taken together these findings could potentially explain different clinical phenotypes in PsA and treatment responses to anti-IL17A (secukinumab, ixekizumab) and IL-17RA (brodalumab) inhibitors furthering support for the use of dual cytokine blockade such as with bimekizumab (Figure 1).

Phase II trials, specifically BE ACTIVE results, have been encouraging. Bimekizumab has shown to be relatively fast-acting, with initial improvements detected by week 8 and well established by week 12. Additionally, at a dose of 160 mg every 4 weeks, bimekizumab has shown to be capable of retaining this level of response in a high percentage of patients for at least 2 years. These results are independent of prior exposure to anti-TNF therapy.10

As with all new drugs, there are still pending questions regarding its optimal use. In BE ACTIVE,10 in which patients received four different dosages through the first 12 weeks, the 160 mg seemed most effective. The initial lower response in the 320 mg group might have been produced by a higher proportion of refractory patients in which bimekizumab took longer to work. This impression is reinforced, in the author’s opinion, by the fact that response rates were different as early as week 4 in both 160 mg (loading dose) and 320 mg dose groups although by that time period both groups had received the same dose. Co-medication was balanced between both groups.

Whichever dose proves best, these results were achieved with mostly mild side-effects that did not lead to treatment discontinuation – most commonly nasopharyngitis, upper respiratory infections and candidiasis. Overall the available data have not revealed any unexpected adverse events. Nonetheless, the number of patients included in the trials is still small. Thirteen out of the 204 patients (6,4%) receiving any dose of bimekizumab in the BE ACTIVE trial had some hepatic adverse effect, raising the need for attentive monitoring by treating physicians. Co-medication needs to be well pondered in this setting as well, but if real-world outcomes of bimekizumab prove as beneficial as in the trials there might be a reduced need for concomitant use of other DMARDs. Although IL-17F has been shown to be associated with increased susceptibility in many forms of human cancer, it has shown a protective role in colon tumorigenesis in mice,32,33 mainly by regulating tumor angiogenesis.6 Longer and bigger trials will be needed to fully ascertain the safety of bimekizumab.

Overall the available results for this new therapeutic option in psoriatic arthritis are encouraging, although it is still early to completely understand the added value offered by bimekizumab. As of yet, however, there are no head-to-head trials directly comparing it to other treatment options in PsA. Anti-IL17A monoclonal antibodies have been evaluated against other therapies, such as anti-TNF inhibitors in the treatment of PsA with mixed results (using different endpoints).34,35

Right now we can only look to early reports from the more advanced Phase 3 trials in psoriasis, where bimekizumab was first studied, which already encompass hundreds of patients and compare bimekizumab with other biologics. A head-to-head comparison with ustekinumab was recently published36 involving 567 patients (321 randomized to bimekizumab, 163 to ustekinumab and 83 to a placebo arm that was switched to bimekizumab at week 16). Using a 320 mg dose of bimekizumab every 4 weeks (and not the 160 mg shown in BE ACTIVE to be the most efficacious in PsA) bimekizumab was superior to ustekinumab (85% vs 49.7% PASI 90 responses at week 16, p<0.001). This response was also sustained throughout the 52-week duration of the study (81.6% vs 55.8%, p<0.001). Similar responses (86.2% vs 47.2% PASI 90 at week 16, p<0.001) in the BE SURE trial comparing bimekizumab (320 mg every 4 weeks or 320 mg until week 16 and then every 8 weeks) and adalimumab (80 mg week 0, 40 mg week 1 and every 2 weeks) were recently presented.37 Switching adalimumab patients to bimekizumab resulted in increased response rates, comparable to rates in bimekizumab-randomized patients at week 56. UCB, the company developing bimekizumab, have also reported the superiority of bimekizumab against secukinumab.38

If nothing else, bimekizumab is a proof-of-concept for a novel avenue in treating inflammatory diseases. Up until now the clinical practice in inflammatory diseases has been to steer clear of the combination of monoclonal antibodies. The results of the trials reported here using bimekizumab to simultaneously inhibit two cytokines, even if related ones, are an important reminder of the redundant and overlapping nature of the immune system and of the multiple pathways through which one arrives at inflammatory disease.

As of yet, however, there are no head-to-head trials directly comparing bimekizumab to conventional DMARDS or other bDMARDs in PsA although the results reported here seem encouraging. Upcoming trials (see Table 2) will hopefully fill this gap in knowledge.

Table 2 Ongoing Trials of Bimekizumab in Psoriatic Arthritis


Psoriatic arthritis can be a severe and disabling disease. Although improvements in its treatment have been achieved in the past decade, its pathogenesis is not completely known, and its treatment is still difficult particularly throughout all disease domains.

The IL-17 pathway has been implicated in disease pathogenesis and targeting IL-17A with secukinumab and ixekizumab has shown good results, although there is still a large proportion of patients that respond only partially. The simultaneous blockade of both IL-17A and IL-17F seems to have a synergistic benefit, with IL-17F inhibition contributing with a differentiated role in both osteogenesis and skin inflammation, important domains of PsA.

Bimekizumab uses a novel approach to biologic treatment in psoriatic arthritis through dual cytokine blockade. Mounting evidence from early trials has shown a good safety and efficacy profile, with rapid onset and sustained response, with results now extending to 108 weeks of follow-up. Moreover, clinical trials in skin psoriasis have also shown that bimekizumab is highly effective, confirming the importance of inhibiting these two cytokines in psoriatic disease.

In the near future, phase III trials will help to better understand the potential of bimekizumab in the treatment of psoriatic arthritis.


  1. Jump up to:a b c d e f “Bimzelx EPAR”European Medicines Agency (EMA). 23 June 2021. Retrieved 24 August 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ^ Lim SY, Oon HH (2019-05-13). “Systematic review of immunomodulatory therapies for hidradenitis suppurativa”Biologics13: 53–78. doi:10.2147/BTT.S199862PMC 6526329PMID 31190730.
  3. ^ “UCB Announces European Commission Approval of Bimzelx (bimekizumab) for the Treatment of Adults with Moderate to Severe Plaque Psoriasis”UCB (Press release). 24 August 2021. Retrieved 24 August 2021.
  4. ^ Warren, Richard B.; Blauvelt, Andrew; Bagel, Jerry; Papp, Kim A.; Yamauchi, Paul; Armstrong, April; Langley, Richard G.; Vanvoorden, Veerle; De Cuyper, Dirk; Cioffi, Christopher; Peterson, Luke (2021-07-08). “Bimekizumab versus Adalimumab in Plaque Psoriasis”New England Journal of Medicine385 (2): 130–141. doi:10.1056/NEJMoa2102388ISSN 0028-4793PMID 33891379.
  5. ^ Reich, Kristian; Warren, Richard B.; Lebwohl, Mark; Gooderham, Melinda; Strober, Bruce; Langley, Richard G.; Paul, Carle; De Cuyper, Dirk; Vanvoorden, Veerle; Madden, Cynthia; Cioffi, Christopher (2021-07-08). “Bimekizumab versus Secukinumab in Plaque Psoriasis”New England Journal of Medicine385 (2): 142–152. doi:10.1056/NEJMoa2102383ISSN 0028-4793PMID 33891380.
  6. ^ World Health Organization (2014). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 72”. WHO Drug Information28 (3). hdl:10665/331112.

Further reading

  • Reis J, Vender R, Torres T (August 2019). “Bimekizumab: The First Dual Inhibitor of Interleukin (IL)-17A and IL-17F for the Treatment of Psoriatic Disease and Ankylosing Spondylitis”. BioDrugs33 (4): 391–9. doi:10.1007/s40259-019-00361-6PMID 31172372S2CID 174812750.

External links

Monoclonal antibody
TypeWhole antibody
Clinical data
Trade namesBimzelx
License dataEU EMAby INN
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
CAS Number1418205-77-2

//////////Bimekizumab, Bimzelx, EU 2021, APPROVALS 2021, Monoclonal antibody
,  plaque psoriasis,ビメキズマブ (遺伝子組換え) , UCB 4940





(Heavy chain)
(Light chain)
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)


トラロキヌマブ (遺伝子組換え)

Mol weight143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,[1] and is designed for the treatment of asthma and other inflammatory diseases.[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354[3] and taken through pre-clinical and early clinical development.[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.[5][6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists[7] using protein optimization based on Ribosome Display.[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.[14]

The applicant for this medicinal product is LEO Pharma A/S.


  1. ^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery9 (9): 703–18. doi:10.1038/nrd2805PMID 20811382S2CID 23769909.
  2. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
  3. ^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America103 (20): 7619–24. Bibcode:2006PNAS..103.7619Tdoi:10.1073/pnas.0602341103PMC 1458619PMID 16684878.
  4. ^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”British Journal of Pharmacology166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.xPMC 3415647PMID 21895629.
  5. ^ “Pipeline”MedImmune. Retrieved 11 June 2013.
  6. ^ “Studies found for CAT-354” Retrieved 11 June 2013.
  7. Jump up to:a b Human Antibody Molecules for Il-13, retrieved 2015-07-26
  8. ^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”Proceedings of the National Academy of Sciences of the United States of America98 (1): 75–80. Bibcode:2001PNAS…98…75Jdoi:10.1073/pnas.98.1.75PMC 14547PMID 11134506.
  9. Jump up to:a b “Tralokinumab”Adis Insight. Springer Nature Switzerland AG.
  10. ^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at
  11. ^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
  12. ^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”The Journal of Allergy and Clinical Immunology143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029PMID 29906525.
  13. ^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis” AstraZeneca. 1 July 2016.
  14. ^ “Adtralza: Pending EC decision”European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y​.
Monoclonal antibody
TypeWhole antibody
Clinical data
ATC codeD11AH07 (WHO)
CAS Number1044515-88-9 
Chemical and physical data
Molar mass143875.20 g·mol−1
  (what is this?)  (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,






(Heavy chain)
(Light chain)
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
>Light Chain
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]


Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21





Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]


Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]


  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – MedNews” Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
CAS Number2022215-59-2
PubChem SID384585344
Chemical and physical data
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Lenalidomide hydrate,

2D chemical structure of 847871-99-2
Lenalidomide enantiomers.svg

Lenalidomide hydrate


An immunomodulator.

CC-5013 hemihydrate

2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

(+/-)-2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

Formula(C13H13N3O3)2. H2O
Mol weight536.5365

EMA APPROVED 2021/2/11,  Lenalidomide KRKA

Research Code:CDC-501; CC-5013

Trade Name:Revlimid®

MOA:Angiogenesis inhibitor

Indication:Myelodysplastic syndrome (MDS); Mantle cell lymphoma (MCL); Multiple myeloma (MM)


Company:Celgene (Originator)

Sales:$5,801.1 Million (Y2015); 
$4,980 Million (Y2014);;
$4280 Million (Y2013);;
$3766.6 Million (Y2012);;
$3208.2 Million (Y2011);ATC Code:L04AX04

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-12-27Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS),Mantle cell lymphoma (MCL)Capsule2.5 mg/5 mg/10 mg/15 mg/20 mg/25 mgCelgenePriority; Orphan


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2007-06-14Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS)Capsule2.5 mg/5 mg/7.5 mg/10 mg/15 mg/20 mg/25 mgCelgeneOrphan


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2010-08-20New indicationRevlimidMyelodysplastic syndrome (MDS)Capsule5 mgCelgene 
2010-06-25Marketing approvalRevlimidMultiple myeloma (MM)Capsule5 mgCelgene 


Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule5 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule10 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule15 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule25 mgCelgene
Molecular Weight259.26
CAS No.191732-72-6 (Lenalidomide);
Chemical Name3(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

Lenalidomide was first approved by the U.S. Food and Drug Administration (FDA) on Dec 27, 2005, then approved by European Medicine Agency (EMA) on June 14, 2007, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on June 25, 2010. It was developed and marketed as Revlimid® by Celgene.

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. Revlimid® is indicated for the treatment of multiple myeloma (MM), in combination with dexamethasone, in patients who have received at least one prior therapy, transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Revlimid® is available as capsule for oral use, containing 2.5, 5, 10, 15, 20 or 25 mg of free Lenalidomide. The recommended dose is 25 mg once daily for multiple myeloma (MM), in combination with 40 mg dexamethasone once daily, 10 mg once daily for myelodysplastic syndromes (MDS) and 25 mg once daily for mantle cell lymphoma (MCL).

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma (MM) and myelodysplastic syndromes (MDS).[2] For MM it is used after at least one other treatment and generally together with dexamethasone.[2] It is taken by mouth.[2]

Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping.[2] Severe side effects may include low blood plateletslow white blood cells, and blood clots.[2] Use during pregnancy may harm the baby.[2] The dose may need to be adjusted in people with kidney problems.[2] It has a chemical structure similar to thalidomide but has a different mechanism of action.[3][2] How it works is not entirely clear as of 2019.[2]

Lenalidomide was approved for medical use in the United States in 2005.[2] It is on the World Health Organization’s List of Essential Medicines.[4]

Medical uses

Multiple myeloma

Lenalidomide is used to treat multiple myeloma.[5] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis.[6][7][8]

Lenalidomide is effective at inducing a complete or “very good partial” response and improves progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma include neutropeniadeep vein thrombosisinfections, and an increased risk of other hematological malignancies.[9] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[10] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[6]

In 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in people with multiple myeloma who have received at least one prior therapy.[11] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.[12]

In 2009, The National Institute for Health and Clinical Excellence issued a final appraisal determination approving lenalidomide in combination with dexamethasone as an option to treat people with multiple myeloma who have received two or more prior therapies in England and Wales.[13]

The use of lenalidomide combined with other drugs was evaluated. It was seen that the drug combinations of lenalidomide plus dexamethasone and continuous bortezomib plus lenalidomide plus dexamethasone probably result in an increase of the overall survival.[14]

Myelodysplastic syndromes

Lenalidomide was approved by the FDA on 27 December 2005 for patients with low- or intermediate-1-risk myelodysplastic syndromes who have chromosome 5q deletion syndrome (5q- syndrome) with or without additional cytogenetic abnormalities.[15][16][17] It was approved on 17 June 2013 by the European Medicines Agency for use in patients with low- or intermediate-1-risk myelodysplastic syndromes who have 5q- deletion syndrome but no other cytogenetic abnormalities and are dependent on red blood cell transfusions, for whom other treatment options have been found to be insufficient or inadequate.[18]

Mantle cell lymphoma

Lenalidomide is approved by FDA as a specialty drug requiring a specialty pharmacy distribution for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies, one of which must have included the medicine bortezomib.[3]


Although not specifically approved by the FDA for use in treating amyloidosis, Lenalidomide is widely used in the treatment of that condition, often in combination with dexamethasone. [19]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism.[3] Serious potential side effects include thrombosispulmonary embolushepatotoxicity, and bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is not the case with thalidomide.[20]

Lenalidomide may be associated with such adverse effects as second primary malignancy, severe cutaneous reactions, hypersensitivity reactionstumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism.[3]


Lenalidomide is related to thalidomide, which is known to be teratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.[21] It cannot be prescribed for women who are pregnant or who may become pregnant during therapy.[1] For this reason, the drug is only available in the United States through a restricted distribution system in conjunction with a risk evaluation and mitigation strategy. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.[3][22]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. High rates of VTE have been found in patients with multiple myeloma who received thalidomide or lenalidomide in conjunction with dexamethasonemelphalan, or doxorubicin.[23]

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of twenty prescription drugs under investigation for potential safety problems. The drug was investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening skin condition.[24]

FDA ongoing safety review

In 2011, the FDA initiated an ongoing review of clinical trials that found an increased risk of developing cancers such as acute myelogenous leukemia and B-cell lymphoma,[25] though it did not advise patients to discontinue treatment with lenalidomide.[26]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.[when?] There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[27] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulationIn vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon[28] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.[29] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.


See also: Development of analogs of thalidomide

Lenalidomide was approved for medical use in the United States in 2005.[2]

Society and culture


Lenalidomide costs US$163,381 per year for the average person in the United States as of 2012.[25] Lenalidomide made almost $9.7bn for Celgene in 2018.[30]

In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for “use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)” in England and Scotland, arguing that Celgene “did not provide enough evidence to justify the GB£3,780 per month (US$5,746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)”.[31]


Lenalidomide is undergoing clinical trial as a treatment for Hodgkin’s lymphoma,[32] as well as non-Hodgkin’s lymphomachronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.[33] One Phase III clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.[34]

SynRoute 1

1. WO9803502A1 / US2002173658A1.

2. Bioorg. Med. Chem. Lett. 19999, 1625-1630.Route 2

1. WO2010139266A1 / US2012077982A1.Route 3

1. CN103497175A.Route 4

1. WO2010139266A1 / US2012077982A1.Route 5

1. CN103554082A.


Alternative synthesis of lenalidomide | SpringerLink


File:Lenalidomide synthesis.png - Wikimedia Commons


Yuri Ponomaryov, Valeria Krasikova, Anton Lebedev, Dmitri Chernyak, Larisa Varacheva, Alexandr Chernobroviy

Cover Image


A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

How to Cite
Ponomaryov, Y.; Krasikova, V.; Lebedev, A.; Chernyak, D.; Varacheva, L.; Chernobroviy, A. Chem. Heterocycl. Compd. 201551, 133. [Khim. Geterotsikl. Soedin. 201551, 133.]

For this article in the English edition see DOI 10.1007/s10593-015-1670-0


A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.


File:Lenalidomide synthesis.png


EP 0925294; US 5635517; WO 9803502

Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).


Bioorg Med Chem Lett 1999,9(11),1625

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.


  • Synonyms:CC-5013, CDC 501
  • ATC:L04AX04
  • MW:259.27 g/mol
  • CAS-RN:191732-72-6
  • InChI:InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)/t10-/m0/s1



  1. Jump up to:a b c “Lenalidomide (Revlimid) Use During Pregnancy” 13 March 2020. Retrieved 13 August 2020.
  2. Jump up to:a b c d e f g h i j k “Lenalidomide Monograph for Professionals” Retrieved 27 October 2019.
  3. Jump up to:a b c d e “DailyMed – Revlimid- lenalidomide capsule” Retrieved 27 October 2019.
  4. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”Journal of Clinical Pharmacy and Therapeutics33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.xPMID 18452408S2CID 1228171.
  6. Jump up to:a b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Current Opinion in Oncology22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752cPMID 20689431S2CID 205547603.
  7. ^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents in Medicinal Chemistry11 (3): 315–26. doi:10.2174/187152011795347487PMID 21426296.
  8. ^ Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, Verma A (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”Journal of Hematology & Oncology2: 36. doi:10.1186/1756-8722-2-36PMC 2736171PMID 19674465.
  9. ^ Yang B, Yu RL, Chi XH, Lu XC (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”PLOS ONE8 (5): e64354. Bibcode:2013PLoSO…864354Ydoi:10.1371/journal.pone.0064354PMC 3653900PMID 23691202.
  10. ^ Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, Morgan GJ (March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”Blood119 (12): 2764–7. doi:10.1182/blood-2011-08-373514PMID 22323483.
  11. ^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.[dead link]
  12. ^ “Lenalidomide (Revlimid)”Food and Drug Administration(FDA). 22 February 2017.
  13. ^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”Reuters. 23 April 2009.
  14. ^ Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, et al. (Cochrane Haematology Group) (November 2019). “Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis”The Cochrane Database of Systematic Reviews2019 (11). doi:10.1002/14651858.CD013487PMC 6876545PMID 31765002.
  15. ^ List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine352 (6): 549–57. doi:10.1056/NEJMoa041668PMID 15703420.
  16. ^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology32 (4 Suppl 5): S31-5. doi:10.1053/j.seminoncol.2005.06.020PMID 16085015.
  17. ^ List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine355 (14): 1456–65. doi:10.1056/NEJMoa061292PMID 17021321.
  18. ^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
  19. ^ “Revlimid and Amyloidosis AL” (PDF). MyelomaUK. Retrieved 3 October 2020.
  20. ^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy64 (17): 1799–807. doi:10.2146/ajhp070029PMID 17724360.
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  24. ^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”Food and Drug Administration(FDA). March 2008. Archived from the original on 19 April 2014. Retrieved 16 December 2019.
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External links[edit]

Clinical data
Trade namesRevlimid, Linamide, others
License dataEU EMAby INNUS DailyMedLenalidomide
AU: X (High risk)[1]
Routes of
By mouth (capsules)
ATC codeL04AX04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-onlyEU: Rx-only
Pharmacokinetic data
Protein binding30%
Elimination half-life3 hours
ExcretionKidney (67% unchanged)
showIUPAC name
CAS Number191732-72-6 
PubChem CID216326
CompTox Dashboard (EPA)DTXSID8046664 
ECHA InfoCard100.218.924 
Chemical and physical data
Molar mass259.265 g·mol−1
3D model (JSmol)Interactive image
ChiralityRacemic mixture
hideInChIInChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18) Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N 

//////////Lenalidomide hydrate, Lenalidomide KRKA, EU 2021, APPROVALS 2021, レナリドミド水和物 , CC-5013 hemihydrate,

#Lenalidomide hydrate, #Lenalidomide KRKA, #EU 2021, #APPROVALS 2021, #レナリドミド水和物 , #CC-5013 hemihydrate,



ChemSpider 2D Image | Setmelanotide | C49H68N18O9S2
SVG Image



  • Molecular FormulaC49H68N18O9S2
  • Average mass1117.309 Da
  • N-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide (2->8)-disulfide

1,2-Dithia-5,8,11,14,17,20-hexaazacyclotricosane-4-carboxamide, 22-[[(2S)-2-(acetylamino)-5-[(diaminomethylene)amino]-1-oxopentyl]amino]-10-[3-[(diaminomethylene)amino]propyl]-16-(1H-imidazol-5-ylmeth yl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-13-(phenylmethyl)-, (4R,7S,10S,13R,16S,19R,22R)- [ACD/Index Name]10011920014-72-8[RN]Imcivree [Trade name]N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-Ltryptophyl- L-cysteinamide, cyclic (2-8)-disulfideN7T15V1FUYRM-493, BIM-22493UNII-N7T15V1FUYсетмеланотид [Russian] [INN]سيتميلانوتيد [Arabic] [INN]司美诺肽 [Chinese] [INN](4R,7S,10S,13R,16S,19R,22R)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide

FDA 11/25/2020, Imcivree, To treat obesity and the control of hunger associated with pro-opiomelanocortin deficiency, a rare disorder that causes severe obesity that begins at an early age
Drug Trials Snapshot, 10MG/ML, SOLUTION;SUBCUTANEOUS, Orphan

Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE™ (setmelanotide) as First-ever Therapy for Chronic Weight Management in Patients with Obesity Due to POMC, PCSK1 or LEPR Deficiency Nasdaq:RYTM

update Imcivree EMA APPROVED 2021/7/16


IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist. Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide α-MSH (alpha-melanocyte stimulating hormone).

The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-Lhistidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide acetate. Its molecular formula is C49H68N18O9S2 (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base).

The chemical structure of setmelanotide is:

IMCIVREE (setmelanotide) Structrual Formula Illustration

IMCIVREE injection is a sterile clear to slightly opalescent, colorless to slightly yellow solution. Each 1 mL of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3phosphoethanolamine sodium salt, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 11 mg mannitol, 5 mg phenol, 10 mg benzyl alcohol, 1 mg edetate disodium dihydrate, and Water for Injection. The pH of IMCIVREE is 5 to 6.

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor. Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects. Setmelanotide increases resting energy expenditure in both obese animals and humans. Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).

Setmelanotide, sold under the brand name Imcivree, is a medication for the treatment of obesity.[1]

The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others.[1] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment.[1] Depression and suicidal ideation have also occurred with setmelanotide.[1]


WO 2011060355

Medical uses

Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.[1] Setmelanotide is the first FDA-approved treatment for these genetic conditions.[1]

Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.[1]

Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects.[2] In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans.[3] Importantly, unlike certain other MC4 receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in heart rate or blood pressure.[4]

Setmelanotide has been reported to possess the following activity profile (cAMPEC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).[5] (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)


Setmelanotide was evaluated in two one-year studies.[1] The first study enrolled participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older.[1] The effectiveness of setmelanotide was determined by the number of participants who lost more than ten percent of their body weight after a year of treatment.[1]

The effectiveness of setmelanotide was assessed in 21 participants, ten in the first study and eleven in the second.[1] In the first study, 80 percent of participants with POMC or PCSK1 deficiency lost ten percent or more of their body weight.[1] In the second study, 46 percent of participants with LEPR deficiency lost ten percent or more of their body weight.[1]

The study also assessed the maximal (greatest) hunger in sixteen participants over the previous 24 hours using an eleven-point scale in participants twelve years and older.[1] In both studies, some, but not all, of participants’ weekly average maximal hunger scores decreased substantially from their scores at the beginning of the study.[1] The degree of change was highly variable among participants.[1]

The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review.[1] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.[1]


Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor.[6][4] Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes.[6] In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity.[7] As of December 2014, the drug is in phase II clinical trials for obesity and PWS.[6][8][9][needs update] So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.[10]


WO 2007008704

WO 2011060355

WO 2011060352

US 20120225816


Journal of Medicinal Chemistry, 61(8), 3674-3684; 2018


Synthesis of Example 1i.e., Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2

Figure US09314509-20160419-C00004

The title peptide having the above structure was assembled using Fmoc chemistry on an Apex peptide synthesizer (Aapptec; Louisville, Ky., USA). 220 mg of 0.91 mmol/g (0.20 mmoles) Rink Amide MBHA resin (Polymer Laboratories; Amherst, Mass., USA) was placed in a reaction well and pre-swollen in 3.0 mL of DMF prior to synthesis. For cycle 1, the resin was treated with two 3-mL portions of 25% piperidine in DMF for 5 and 10 minutes respectively, followed by 4 washes of 3-mL DMF—each wash consisting of adding 3 mL of solvent, mixing for 1 minute, and emptying for 1 minute. Amino acids stocks were prepared in NMP as 0.45M solutions containing 0.45M HOBT. HBTU was prepared as a 0.45M solution in NMP and DIPEA was prepared as a 2.73M solution in NMP. To the resin, 2 mL of the first amino acid (0 9 mmoles, Fmoc-Cys(Trt)-OH) (Novabiochem; San Diego, Calif., USA) was added along with 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA. After one hour of constant mixing, the coupling reagents were drained from the resin and the coupling step was repeated. Following amino acid acylation, the resin was washed with two 3-mL aliquots of DMF for 1 minute. The process of assembling the peptide (deblock/wash/acylate/wash) was repeated for cycles 2-9 identical to that as described for cycle 1. The following amino acids were used: cycle 2) Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); cycle 3) Fmoc-Arg(Pbf)-OH (Novabiochem); cycle 4) Fmoc-DPhe-OH (Genzyme); cycle 5) Fmoc-His(Trt)-OH (Novabiochem); cycle 6) Fmoc-D-Ala-OH (Genzyme); cycle 7) Fmoc-Cys(Trt)-OH, (Novabiochem); and cycle 8) Fmoc-Arg(Pbf)-OH (Genzyme). The N-terminal Fmoc was removed with 25% piperidine in DMF as described above, followed by four 3-mL DMF washes for 1 minute. Acetylation of the N-terminus was performed by adding 0.5 mL of 3M DIPEA in NMP to the resin along with 1.45 mL of 0.45M acetic anhydride in NMP. The resin was mixed for 30 minutes and acetylation was repeated. The resin was washed with 3 mL of DMF for a total of 5 times followed with 5 washes with 5 mL of DCM each.

To cleave and deprotect the peptide, 5mL of the following reagent was added to the resin: 2% TIS/5% water/5% (w/v) DTT/88% TFA. The solution was allowed to mix for 3.5 hours. The filtrate was collected into 40 mL of cold anhydrous ethyl ether. The precipitate was pelleted for 10 minutes at 3500 rpm in a refrigerated centrifuge. The ether was decanted and the peptide was re-suspended in fresh ether. The ether workup was performed three times. Following the last ether wash, the peptide was allowed to air dry to remove residual ether.

The peptide was dissolved in 10% acetonitrile and analyzed by mass spectrometry and reverse-phase HPLC employing a 30×4.6 cm C18 column (Vydac; Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile (0.1% TFA) over 30 minutes. This analysis identified a product with ˜53% purity. Mass analysis employing electrospray ionization identified a main product containing a mass of 1118.4 corresponding to the desired linear product. The crude product (˜100 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid. To this solution, 0.5M iodine/methanol was added dropwise with vigorous stirring until a pale yellow color was achieved. The solution was vigorously stirred for another 10 minutes. Excess iodine was then quenched by adding 1.0M sodium thiosulfate under continuous mixing until the mixture was rendered colorless. The peptide was re-examined by mass spectrometry analysis and HPLC. Mass spectrometry analysis identified a main species with a mass of 1116.4 which indicated successful oxidation to form the cyclic peptide. The peptide solution was purified on a preparative HPLC equipped with a C18 column using a similar elution gradient. The purified product was re-analyzed by HPLC for purity (>95%) and mass spectrometry (1116.9 which is in agreement with the expected mass of 1117.3) and subsequently lyophilized. Following lyophilization, 28 mg of purified product was obtained representing a 24% yield.

The other exemplified peptides were synthesized substantially according to the procedure described for the above-described synthetic process. Physical data for select exemplified peptides are given in Table 1.

TABLE 1 Example Mol. Wt. Mol. Wt. Purity Number (calculated) (ES-MS) (HPLC) 1 1117.3 1116.9 95.1% 2 1117.3 1116.8 99.2% 3 1280.5 1280.6 98.0% 5 1216.37 1216.20 99.9%

Preparation of Pamoate Salt of Example 1

The acetate salt of Example 1 (200 mg, 0.18 mmole) was dissolved in 10 mL of water. Sodium pamoate (155 mg, 0.36 mmole) was dissolved in 10 mL of water. The two solutions were combined and mixed well. The precipitates were collected by centrifugation at 3000 rpm for 20 minutes, washed for three times with water, and dried by lyophilization.


  1. Jump up to:a b c d e f g h i j k l m n o p q r “FDA approves first treatment for weight management for people with certain rare genetic conditions”U.S. Food and Drug Administration (FDA) (Press release). 27 November 2020. Retrieved 27 November 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ Kim GW, Lin JE, Blomain ES, Waldman SA (January 2014). “Antiobesity pharmacotherapy: new drugs and emerging targets”Clinical Pharmacology and Therapeutics95 (1): 53–66. doi:10.1038/clpt.2013.204PMC 4054704PMID 24105257.
  3. ^ Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. (April 2015). “RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals”The Journal of Clinical Endocrinology and Metabolism100 (4): 1639–45. doi:10.1210/jc.2014-4024PMC 4399297PMID 25675384.
  4. Jump up to:a b Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. (February 2013). “Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques”Diabetes62 (2): 490–7. doi:10.2337/db12-0598PMC 3554387PMID 23048186.
  5. ^ Muniyappa R, Chen K, Brychta R, Abel B, Mullins K, Staker P, et al. (June 2014). “A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of a Melanocortin Receptor 4 (MC4R) Agonist, RM-493, on Resting Energy Expenditure (REE) in Obese Subjects” (PDF). Endocrine Reviews. Rhythm Pharmaceuticals. 35 (3). Retrieved 2015-05-21.
  6. Jump up to:a b c Lee EC, Carpino PA (2015). “Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)”. Pharmaceutical Patent Analyst4 (2): 95–107. doi:10.4155/ppa.15.1PMID 25853469.
  7. ^ “Obesity and Diabetes Caused by Genetic Deficiencies in the MC4 Pathway”. Rhythm Pharmaceuticals. Retrieved 2015-05-21.
  8. ^ Jackson VM, Price DA, Carpino PA (August 2014). “Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies”. Expert Opinion on Investigational Drugs23 (8): 1055–66. doi:10.1517/13543784.2014.918952PMID 25000213S2CID 23198484.
  9. ^ “RM-493: A First-in-Class, Phase 2-Ready MC4 Agonist: A New Drug Class for the Treatment of Obesity and Diabetes”. Rhythm Pharmaceuticals. Archived from the original on 2015-06-14. Retrieved 2015-05-21.
  10. ^ Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, et al. (March 2019). “A multidisciplinary approach to the clinical management of Prader-Willi syndrome”Molecular Genetics & Genomic Medicine7 (3): e514. doi:10.1002/mgg3.514PMC 6418440PMID 30697974.


The peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It is being researched by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II clinical trials for obesity and PWS.

L-Cysteinamide, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-, cyclic (2->8)-disulfide


1: Lee EC, Carpino PA. Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014). Pharm Pat Anal. 2015;4(2):95-107. doi: 10.4155/ppa.15.1. PubMed PMID: 25853469.

2: Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, Zhao X, Ring M, Psota TL, Cone RD, Panaro BL, Gottesdiener KM, Van der Ploeg LH, Reitman ML, Skarulis MC. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45. doi: 10.1210/jc.2014-4024. Epub 2015 Feb 12. PubMed PMID: 25675384; PubMed Central PMCID: PMC4399297.

3: Clemmensen C, Finan B, Fischer K, Tom RZ, Legutko B, Sehrer L, Heine D, Grassl N, Meyer CW, Henderson B, Hofmann SM, Tschöp MH, Van der Ploeg LH, Müller TD. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med. 2015 Feb 4;7(3):288-98. doi: 10.15252/emmm.201404508. PubMed PMID: 25652173; PubMed Central PMCID: PMC4364946.

4: Jackson VM, Price DA, Carpino PA. Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies. Expert Opin Investig Drugs. 2014 Aug;23(8):1055-66. doi: 10.1517/13543784.2014.918952. Epub 2014 Jul 7. Review. PubMed PMID: 25000213.

5: Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013 Feb;62(2):490-7. doi: 10.2337/db12-0598. Epub 2012 Oct 9. PubMed PMID: 23048186; PubMed Central PMCID: PMC3554387.

6: Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900. doi: 10.1016/j.peptides.2009.07.012. Epub 2009 Jul 29. PubMed PMID: 19646498; PubMed Central PMCID: PMC2755620.

External links

Clinical data
Trade namesImcivree
Other namesRM-493; BIM-22493; IRC-022493; N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide
ATC codeNone
Legal status
Legal statusUS: ℞-only
IUPAC name[show]
CAS Number920014-72-8
PubChem CID11993702
Chemical and physical data
Molar mass1117.32 g·mol−1
3D model (JSmol)Interactive image

///////////Setmelanotide, FDA 2020, 2020 APPROVALS, Imcivree, Orphan, PEPTIDE, ANTIOBESITY, UNII-N7T15V1FUY, сетмеланотид , سيتميلانوتيد , 司美诺肽 , BIM 22493, RM 493






A-4250, AR-H 064974

CAS 501692-44-0


(2S)-2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,2,5-benzothiadiazepin-8-yl)oxy]acetyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]butanoic acid

Molecular Formula C37H48N4O8S2
Molecular Weight 740.929
        • UPDATE 7/20/2021FDA APPROVED, To treat pruritus,


    • New Drug Application (NDA): 215498
  • Orphan Drug Status Yes – Primary biliary cirrhosis; Biliary atresia; Intrahepatic cholestasis; Alagille syndrome
  • New Molecular Entity Yes
  • Phase III Biliary atresia; Intrahepatic cholestasis
  • Phase II Alagille syndrome; Cholestasis; Primary biliary cirrhosis
  • No development reported Non-alcoholic steatohepatitis
  • 22 Jul 2020 Albireo initiates an expanded-access programme for Intrahepatic cholestasis in USA, Canada, Australia and Europe
  • 14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Belgium (PO) after July 2020 (EudraCT2019-003807-37)
  • 14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Germany, France, United Kingdom, Hungary (PO) (EudraCT2019-003807-37)

UPDATE Bylvay, FDA APPROVED2021/7/20 AND EMA 2021/7/16

Odevixibat, sold under the trade name Bylvay, is a medication for the treatment of progressive familial intrahepatic cholestasis (PFIC).[1]

The most common side effects include diarrhea, abdominal pain, hemorrhagic diarrhea, soft feces, and hepatomegaly (enlarged liver).[1]

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).[1][2]

In May 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a marketing authorization in the European Union for odevixibat for the treatment of PFIC in people aged six months or older.[1][3]

A-4250 (odevixibat) is a selective inhibitor of the ileal bile acid transporter (IBAT) that acts locally in the gut. Ileum absorbs glyco-and taurine-conjugated forms of the bile salts. IBAT is the first step in absorption at the brush-border membrane. A-4250 works by decreasing the re-absorption of bile acids from the small intestine to the liver, whichreduces the toxic levels of bile acids during the progression of the disease. It exhibits therapeutic intervention by checking the transport of bile acids. Studies show that A-4250 has the potential to decrease the damage in the liver cells and the development of fibrosis/cirrhosis of the liver known to occur in progressive familial intrahepatic cholestasis. A-4250 is a designated orphan drug in the USA for October 2012. A-4250 is a designated orphan drug in the EU for October 2016. A-4250 was awarded PRIME status for PFIC by EMA in October 2016. A-4250 is in phase II clinical trials by Albireo for the treatment of primary biliary cirrhosis (PBC) and cholestatic pruritus. In an open label Phase 2 study in children with cholestatic liver disease and pruritus, odevixibat showed reductions in serum bile acids and pruritus in most patients and exhibited a favorable overall tolerability profile.



Odevixibat is a highly potent, non-systemic ileal bile acid transport inhibitor (IBATi) that has has minimal systemic exposure and acts locally in the small intestine. Albireo is developing odevixibat to treat rare pediatric cholestatic liver diseases, including progressive familial intrahepatic cholestasisbiliary atresia and Alagille syndrome.

With normal function, approximately 95 percent of bile acids released from the liver into the bile ducts to aid in liver function are recirculated to the liver via the IBAT in a process called enterohepatic circulation. In people with cholestatic liver diseases, the bile flow is interrupted, resulting in elevated levels of toxic bile acids accumulating in the liver and serum. Accordingly, a product capable of inhibiting the IBAT could lead to a reduction in bile acids returning to the liver and may represent a promising approach for treating cholestatic liver diseases.

The randomized, double-blind, placebo-controlled, global multicenter PEDFIC 1 Phase 3 clinical trial of odevixibat in 62 patients, ages 6 months to 15.9 years, with PFIC type 1 or type 2 met its two primary endpoints demonstrating that odevixibat reduced serum bile acids (sBAs) (p=0.003) and improved pruritus (p=0.004), and was well tolerated with a low single digit diarrhea rate. These topline data substantiate the potential for odevixibat to be first drug for PFIC patients. The Company intends to complete regulatory filings in the EU and U.S. no later than early 2021, in anticipation of regulatory approval, issuance of a rare pediatric disease priority review voucher and launch in the second half of 2021.

Odevixibat is being evaluated in the ongoing PEDFIC 2 open-label trial (NCT03659916) designed to assess long-term safety and durability of response in a cohort of patients rolled over from PEDFIC 1 and a second cohort of PFIC patients who are not eligible for PEDFIC 1.

Odevixibat is also currently being evaluated in a second Phase 3 clinical trial, BOLD (NCT04336722), in patients with biliary atresia. BOLD, the largest prospective intervention trial ever conducted in biliary atresia, is a double-blind, randomized, placebo-controlled trial which will enroll approximately 200 patients at up to 75 sites globally to evaluate the efficacy and safety of odevixibat in children with biliary atresia who have undergone a Kasai procedure before age three months. The company also anticipates initiating a pivotal trial of odevixibat for Alagille syndrome by the end of 2020.

For more information about the PEDFIC 2 or BOLD studies, please visit or contact

The odevixibat PFIC program, or elements of it, have received fast track, rare pediatric disease and orphan drug designations in the United States. In addition, the FDA has granted orphan drug designation to odevixibat for the treatment of Alagille syndrome, biliary atresia and primary biliary cholangitis. The EMA has granted odevixibat orphan designation, as well as access to the PRIority MEdicines (PRIME) scheme for the treatment of PFIC. Its Paediatric Committee has agreed to Albireo’s odevixibat Pediatric Investigation Plan for PFIC. EMA has also granted orphan designation to odevixibat for the treatment of biliary atresia, Alagille syndrome and primary biliary cholangitis.


Example 5

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 740.94.

This compound is prepared as described in Example 29 of WO3022286.


Example 29

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-((R)-α-[N-((S)- 1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example 18; 0.075 g, 0.114 mmol), butanoic acid, 2-amino-, 1,1-dimethylethyl ester, hydrochloride, (2S)-(0.031 g, 0.160 mmol) and Ν-methylmorpholine (0.050 ml, 0.457 mmol) in DMF (4 ml) was stirred at RT for 10 min, after which TBTU (0.048 g, 0.149 mmol) was added. After 1h, the conversion to the ester was complete. M/z: 797.4. The solution was diluted with toluene and then concentrated. The residue was dissolved in a mixture of DCM (5 ml) and TFA (2 ml) and the mixture was stirred for 7h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-60% MeCΝ in 0.1M ammonium acetate buffer as eluent. The title compound was obtained in 0.056 g (66 %) as a white solid. ΝMR (400 MHz, DMSO-d6): 0.70 (3H, t), 0.70-0.80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.80 (2H, brs), 4.00-4.15 (1H, m), 4.65 (1H, d(AB)), 4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.65-7.40 (11H, m), 8.35 (1H, d), 8.50 (1H, d) 9.40 (1H, brs).




The compound l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(A/-{(R)-a-[A/-((S)-l-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,2,5-benzothiadiazepine (odevixibat; also known as A4250) is disclosed in WO 03/022286. The structure of odevixibat is shown below.

Figure imgf000002_0001

As an inhibitor of the ileal bile acid transporter (IBAT) mechanism, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted into the faeces. The overall removal of bile acids from the enterohepatic circulation leads to a decrease in the level of bile acids in serum and the liver. Odevixibat, or a pharmaceutically acceptable salt thereof, is therefore useful in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases, and especially liver diseases that are associated with elevated bile acid levels.

According to the experimental section of WO 03/022286, the last step in the preparation of odevixibat involves the hydrolysis of a tert-butyl ester under acidic conditions. The crude compound was obtained by evaporation of the solvent under reduced pressure followed by purification of the residue by preparative HPLC (Example 29). No crystalline material was identified.

Amorphous materials may contain high levels of residual solvents, which is highly undesirable for materials that should be used as pharmaceuticals. Also, because of their lower chemical and physical stability, as compared with crystalline material, amorphous materials may display faster

decomposition and may spontaneously form crystals with a variable degree of crystallinity. This may result in unreproducible solubility rates and difficulties in storing and handling the material. In pharmaceutical preparations, the active pharmaceutical ingredient (API) is for that reason preferably used in a highly crystalline state. Thus, there is a need for crystal modifications of odevixibat having improved properties with respect to stability, bulk handling and solubility. In particular, it is an object of the present invention to provide a stable crystal modification of odevixibat that does not contain high levels of residual solvents, that has improved chemical stability and can be obtained in high levels of crystallinity.

Example 1

Preparation of crystal modification 1

Absolute alcohol (100.42 kg) and crude odevixibat (18.16 kg) were charged to a 250-L GLR with stirring under nitrogen atmosphere. Purified water (12.71 kg) was added and the reaction mass was stirred under nitrogen atmosphere at 25 ± 5 °C for 15 minutes. Stirring was continued at 25 ± 5 °C for 3 to 60 minutes, until a clear solution had formed. The solution was filtered through a 5.0 m SS cartridge filter, followed by a 0.2 m PP cartridge filter and then transferred to a clean reactor.

Purified water (63.56 kg) was added slowly over a period of 2 to 3 hours at 25 ± 5 °C, and the solution was seeded with crystal modification 1 of odevixibat. The solution was stirred at 25 ± 5 °C for 12 hours. During this time, the solution turned turbid. The precipitated solids were filtered through centrifuge and the material was spin dried for 30 minutes. The material was thereafter vacuum dried in a Nutsche filter for 12 hours. The material was then dried in a vacuum tray drier at 25 ± 5 °C under vacuum (550 mm Hg) for 10 hours and then at 30 ± 5 °C under vacuum (550 mm Hg) for 16 hours. The material was isolated as an off-white crystalline solid. The isolated crystalline material was milled and stored in LDPE bags.

An overhydrated sample was analyzed with XRPD and the diffractogram is shown in Figure 2.

Another sample was dried at 50 °C in vacuum and thereafter analysed with XRPD. The diffractogram of the dried sample is shown in Figure 1.

The diffractograms for the drying of the sample are shown in Figures 3 and 4 for 2Q ranges 5 – 13 ° and 18 – 25 °, respectively (overhydrated sample at the bottom and dry sample at the top).


  1. Jump up to:a b c d “First treatment for rare liver disease”European Medicines Agency (EMA) (Press release). 21 May 2021. Retrieved 21 May 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ^ “Odevixibat”Albireo Pharma. Retrieved 21 May 2021.
  3. ^ “Bylvay: Pending EC decision”European Medicines Agency (EMA). 19 May 2021. Retrieved 21 May 2021.

External links

  • “Odevixibat”Drug Information Portal. U.S. National Library of Medicine.

CTID Title Phase Status Date
NCT04336722 Efficacy and Safety of Odevixibat in Children With Biliary Atresia Who Have Undergone a Kasai HPE (BOLD) Phase 3 Recruiting 2020-09-02
NCT04483531 Odevixibat for the Treatment of Progressive Familial Intrahepatic Cholestasis Available 2020-08-25
NCT03566238 This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC 1 or 2 Phase 3 Active, not recruiting 2020-03-05
NCT03659916 Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC Phase 3 Recruiting 2020-01-21
NCT03608319 Study of A4250 in Healthy Volunteers Under Fasting, Fed and Sprinkled Conditions Phase 1 Completed 2018-09-19
CTID Title Phase Status Date
NCT02630875 A4250, an IBAT Inhibitor in Pediatric Cholestasis Phase 2 Completed 2018-03-29
NCT02360852 IBAT Inhibitor A4250 for Cholestatic Pruritus Phase 2 Terminated 2017-02-23
NCT02963077 A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384 Phase 1 Completed 2016-11-16

EU Clinical Trials Register

EudraCT Title Phase Status Date
2019-003807-37 A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children with Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy (BOLD) Phase 3 Ongoing 2020-07-29
2015-001157-32 An Exploratory Phase II Study to demonstrate the Safety and Efficacy of A4250 Phase 2 Completed 2015-05-13
2014-004070-42 An Exploratory, Phase IIa Cross-Over Study to Demonstrate the Efficacy Phase 2 Ongoing 2014-12-09
2017-002325-38 An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 2) Phase 3 Ongoing
2017-002338-21 A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1) Phase 3 Ongoing, Completed


Odevixibat structure.png
Clinical data
Trade names Bylvay
Routes of
By mouth
ATC code
  • None
CAS Number
  • 501692-44-0
PubChem CID
Chemical and physical data
Formula C37H48N4O8S2
Molar mass 740.93 g·mol−1
3D model (JSmol)

////////////odevixibat, Orphan Drug Status, phase 3, Albireo, A-4250, A 4250, AR-H 064974


US-2020046636-A1 US-2020046757-A1 US-2020046758-A1 US-2020002299-A1 WO-2019245448-A1 WO-2019245449-A1 US-2019046451-A1 US-2019070217-A1


Remimazolam.svgChemSpider 2D Image | Remimazolam | C21H19BrN4O2GHUYIIGPWBMOGY-KRWDZBQOSA-N.png

Figure imgf000062_0002


  • Molecular FormulaC21H19BrN4O2
  • Average mass439.305 Da
3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid methyl ester
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(7S)-12-bromo-3-methyl-9-(pyridin-2-yl)-2,5,8-triazatricyclo[,6]tetradeca-1(14),3,5,8,10,12-hexaen-7-yl]propanoate

CAS 308242-62-8 [RN]

PHASE 3, PAION, Anesthesia

Approved 2021/3/26 eu Byfavo

4H-Imidazo[1,2-a][1,4]benzodiazepine-4-propanoic acid, 8-bromo-1-methyl-6-(2-pyridinyl)-, methyl ester, (4S)-

Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-2-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
D0L5KU; GTPL8442; SCHEMBL13862667; Short-acting sedatives, Therasci; CNS-7056B; CNS-7056X
  1. CNS 7056
  2. methyl 3-(8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo(1,2-a)(1,4)benzodiazepin-4-yl)propanoate
  3. ONO 2745
  4. ONO-2745
  5. ONO2745

Remimazolam[1] (CNS-7056) is a benzodiazepine derivative drug, developed by PAION, in collaboration with Japanese licensee Ono Pharmaceutical as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in induction of anaesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to be both faster acting and shorter lasting than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.[2][3]

Remimazolam (CNS-7056) is a water-soluble, rapid and short-acting GABA (A) benzodiazepine (BZ) site receptor agonist in phase III trials at PAION as procedural sedation in patients undergoing colonoscopy or diagnostic endoscopy of the upper gastrointestinal tract, and also with patients undergoing bronchoscopy.

PAION AG and its subsidiary PAION Inc, following its acquisition of CeNeS Pharmaceuticals (following CeNeS’ acquisition of TheraSci ), and licensees Mundipharma , Yichang Humanwell Pharmaceutical , Pendopharm , Cosmo and R-Pharm are developing remimazolam, the lead from a series of short-acting GABA A receptor agonists, as an iv sedative and/or anesthetic for potential use in day case surgical and non-surgical procedures

Image result for remimazolam

Remimazolam [INN]
2D chemical structure of 308242-62-8
MW: 439.3111
Remimazolam besilate
2D chemical structure of 1001415-66-2
MW: 597.4875
Remimazolam tosylate
2D chemical structure of 1425904-79-5
MW: 611.5143


Phase I[4] and Ib[5] dose-finding studies for procedural sedation with patients recovering faster from remimazolam than midazolam. Phase II trials comparing remimazolam to the standard anesthesia protocols for cardiac surgery and colonoscopy were presented at major conferences in October 2014.[6]

A phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile.[7] Remimazolam was originally discovered in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, NC.



Novel crystalline forms of hydrobromate salt of remimazolam , processes for their preparation and compositions comprising them are claimed.

Remazolam, whose structure is shown in formula (I), has the chemical name 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole [1,2] -a] methyl [1,4]benzodiazepin- 4-yl]propanoate.
This compound is currently known as a CNS (Central Nervous System) inhibitor and has sedative, hypnotic, anxiolytic, muscle relaxing, and anticonvulsant effects. It is currently used intravenously in the following clinical treatment programs: preoperative sedation, anxiolysis and forgetfulness during surgery; awake sedation during short-term diagnosis, surgery, or endoscopic procedures; and administration of other anesthetics and analgesia Before and/or at the same time as a component for induction and maintenance of general anesthesia; ICU sedation and the like. It is reported in patent application CN101501019 that the free base stability of the compound is poor, and it is only suitable for storage at a low temperature of 5°C. Under conditions of 40°C/75% relative humidity (open), the sample is deliquescent and discolored, and the content is significantly reduced.
Due to the stability problem of the free base of the compound, researchers from various countries have studied the salts of the compound. For example, patent applications CN101501019B and WO2008/007081A1 respectively report the besylate and ethanesulfonate of the compound of formula (I). And shows that the above salts have good thermal stability, low hygroscopicity, and high water solubility, and that CN104968348A clearly states that the above benzenesulfonates and ethanesulfonates are the most preferred compounds of formula (I). Salts.
Immediately afterwards, CN 103221414B proposes a toxilate salt of a compound of formula (I) and indicates that the toxitic acid salt is less toxic than benzene sulphonate, and the thermal stability, water solubility and the like of certain crystal forms are even higher. For good.
To sort out the existing technology information, you can draw the following related content (Table 1):
Table 1
From the above table, it can be seen that regardless of whether it is a free base of remazolam or a known salt derivative of remazolam, the water solubility is not higher than 11 mg/ml, and only in the slightly soluble range, which will increase The safety risk of its use in clinical use requires resolving and dissolving for a long time during clinical reconstitution. It may also leave insoluble materials, resulting in inaccurate drug dosage and potential safety risks. In addition, it is used for general anesthesia. Indications with a large demand will increase the amount of diluent and cause extreme inconvenience for clinical use. Therefore, the solubility of the known salt derivatives of remazolam is a big disadvantage and needs to be further improved.
The raw material remazolam of the compound of the formula (I) used in the present invention can be obtained by purchasing a commercially available product or can be prepared according to a known method (for example, patent US200,700,934,75A, etc.).
Example 1 Preparation of Form III Hydrobromide Salt of Compound of Formula (I)
Accurately weigh 1.8 g of the compound of formula (I) into a 100 mL three-necked flask, add 8.2 mL of isopropanol and stir to dissolve it completely, then dissolve 0.83 g of 47% aqueous hydrobromic acid in 6.3 mL of isopropanol and drip To the solution of the compound of formula (I) in isopropanol, the crystals were stirred, filtered, and dried at 55°C under reduced pressure to give the hydrobromide salt of the compound of formula (I).
The X-ray diffraction pattern of this crystal is shown in FIG. 1, the DSC and TGA patterns are shown in FIG. 2, and the melting point is 163 DEG C. It is defined that the crystal form is the hydrobromide III crystal form of the compound of Formula (I).



Family members of remimazolam’s product case WO0069836 , have production in most of the EU states until May 2020 and expire in the US in April 2020.


WO 2000069836

Inventors Paul L. FeldmanDavid Kendall JungIstvan KaldorGregory J. PacofskyJeffrey A. StaffordJeffrey H. TidwellLess «
Applicant Glaxo Group Limited

Example Ic-8

Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate

Figure imgf000062_0002

A solution of the C7-bromo-benzodiazepine Ex 1-10 (7.31 g, 18.2 mmol) in THF (21 mL) was added to a suspension of NaH (870 mg of 60% oil dispersion, 21.8 mmol) in THF (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature and stirred for 30 min, then cooled to 0 °C. Bis- morpholinophosphorochloridate (6.48 g, 25.5 mmol) was added, the mixture was allowed to warm to room temperature over 4.5 h, and the mixture was filtered with additional THF (ca. 10 mL). A mixture of the filtrate and DL-l-amino-2-propanol (2.80 mL, 36.4 mmol) was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was diluted with EtOAc (ca. 250 mL), washed with saturated aqueous NaHCO3 (1 x 75 mL), H2O (2 x 75 mL), saturated aqueous NaCl (1 x 75 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave 3.06 g

(37%) of the adduct as a foam; ESIMS 459 (M+H, base).

A mixture of DMSO (1.88 mL, 26.6 mmol) and oxalyl chloride (1.16 mL, 13.3 mmol) in CH2C12 (40 mL) was stirred at -78 °C for 30 min. A solution of the alcohol prepared above (3.05 g, 6.64 mmol) in CH2C1 (26 mL) was added. The reaction mixture was warmed to -15 °C and stirred 1 h, cooled to -78 °C, treated with

E-3N (5.55 mL, 39.9 mmol), and allowed to warm to room temperature over 3 h. The mixture was diluted with EtOAc (ca. 500 mL), washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (1 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure to give a foam. A mixture of this foam and a catalytic amount ofp-toluenesulfonic acid was stirred at room temperature for 18h, neutralized by the addition of saturated aqueous NaHCO3 and diluted with EtOAc (ca. 500 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (2 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19: 1 EtOAc-

MeOH, gave 2.56 g (88%) of Ic-8 as a foam; 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 4.6 Hz, lH), 8.17 (d J = 7.8 Hz, IH), 7.79 (dd, J = 7.7, 6.2 Hz, IH), 7.71 (dd, J = 8.6, 2.2 Hz, IH), 7.64 (d, J – 2.2 Hz, IH), 7.34 (dd, J = 7.5, 5.0 Hz, IH), 7.30 (d, J = 8.6 Hz, IH), 6.86 (s, IH), 4.05 (m, 1 H), 3.67 (s, 3H), 2.80 (comp, 4H), 2.34 (s, 3H); ESIMS 461 (M+Na, base), 439 (M+H); Anal, calcd. for C2]H19BrN4O2-0.25 H2O: C,

58.63; H, 4.43; N, 12.62. Found: C, 56.88; H, 4.43; N, 12.23.

Example lc-8 was formulated in an aqueous vehicle at a concentration of 10 mg/ml. Accordingly, 10 mg of compound (and 9 mg NaCl) was dissolved in 0.63 ml of 0.1 N HCl. Slowly and while stirring, 0.37 ml of 0.1 N NaOH was added. Adjustments are made to the dose volume depending on the dose being administered.


CN 103232454

The compounds of the following formula I:


Figure CN103232454AD00051

Wherein R1 is bromine, R2 and R3 is methyl, [0004] because it contains the specific configuration, W000 / 69836 reported in the compound (60 specification Example Ic-8) is a short-acting central nervous system (CNS) to suppress agents, including having a sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effect.They can be used for intravenous administration in the clinical treatment: preoperative sedation, such as during surgery, and forgetting anxiolytic purposes; in short diagnostic, operative or endoscopic conscious sedation during the procedure; administration of other anesthetics and analgesics before and / or simultaneously, as a component for the induction and maintenance of general anesthesia in; the ICU sedation, according CN101501019A (PA10N, application No. CN200780028964.5) reports, free base of the compound is not very stable, only suitable stored at low temperatures 5 ° C, at 40 ° C / 75% relative humidity (open) condition, the sample storage deliquescence, to the orange color turned yellow, with respect to the initial content and significantly reduced the content of the display. Thus the synthesis of salts of compounds of formula It (the I), hoping to increase the chemical stability thereof, for use in the preparation of medicaments.

[0005] existing CN101501019A and US20100075955A1 (TILBR00K) reported the benzenesulfonate salt of a compound of formula I, ethanesulfonate.CN102964349A (Henry, Application No. 201110456864.0) reported for compounds of formula ITosylate.

[0006] have reported the presence of a compound of formula I or a salt thereof concerns stability, which is disadvantageous for these compounds used in the clinical treatment of related diseases.

HPLC method [A]:

[0022] According to Chinese Pharmacopoeia 2010 Appendix VD High Performance Liquid Chromatography;

[0023] using Daicel Chrialcel OJ-H (5 μ m) 4.6 X 250mm using chiral chromatographic columns (guard column, if necessary Daicel Chrialcel OJ-H column analysis protected 5 μ m4.0 X IOmm, which is Japan Series Cat (Daicel ) brand), hexane: ethanol = 93: 7 (v / v) as the mobile phase, a flow rate of 1.0ml / min, column temperature 40 ° C, detection wavelength 225nm;

Bulk drug preparation of the present invention: [0204] Example 1

[0205] Preparation Example 4 taking the resulting compound of formula I lg, were added to 8ml of ethanol at 50 ° C – lactic acid – water (volume ratio of the three 45: 2: 53) mixed solution was stirred to dissolve; filtration, the filtrate was 5 ° C was allowed to stand at a temperature of 10~12 hours recrystallized, crystals were filtered off, 40 ° C and dried in vacuo; the above operation was repeated once, to give a compound of formula I may be formulated bulk drug used as a pharmaceutical formulation, was recrystallized twice yield rate of 86.1%.Chromatographic purity of product by HPLC 99.22% [B]; R & lt isomer impurity content of 0.39% relative peak area ratio (I / Ix) = 255 HPLC [Method A].


EP 2305647


WO 2011032692,

See also


  1. Jump up^ EP Patent 1183243
  2. Jump up^ Rogers WK, McDowell TS (December 2010). “Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures”. IDrugs : the Investigational Drugs Journal13 (12): 929–37. PMID 21154153.
  3. Jump up^ Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT (March 2011). “Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology”. Pharmacological Reviews63 (1): 243–67. doi:10.1124/pr.110.002717PMID 21245208.
  4. Jump up^ “A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics”. Anesth. Analg.accessdate =115: 274–83. Aug 2012. doi:10.1213/ANE.0b013e31823f0c28PMID 22190555.
  5. Jump up^ “A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy”. Anesth. Analg117: 1093–100. Nov 2013. doi:10.1213/ANE.0b013e3182a705aePMID 24108261.
  6. Jump up^ “Two Scientific Remimazolam Presentations Are Accepted for ASA and ACG Meeting in October 2014”MarketWired. Oct 1, 2014. Retrieved 2014-10-24.
  7. Jump up^ “A Phase IIa, Randomized, Double-Blind Study of Remimazolam (CNS 7056) Versus Midazolam for Sedation in Upper Gastrointestinal Endoscopy”. Anesthesia120: 771–80. Dec 11, 2014. doi:10.1213/ANE.0000000000000548PMID 25502841


WO2016011943A1 *2014-07-232016-01-28李勤耕New benzodiazepine derivative and use thereof

WO2000069836A1 *1999-05-142000-11-23Glaxo Group LimitedShort-acting benzodiazepines
WO2008007081A1 *2006-07-102008-01-17Cenes LimitedShort-acting benzodiazepine salts and their polymorphic forms
CN101501019A *2006-07-102009-08-05Paion英国有限公司Short-acting benzodiazepine salts and their polymorphic forms
WO2012062439A1 *2010-11-082012-05-18Paion Uk Ltd.Dosing regimen for sedation with cns 7056 (remimazolam)
CN102753525A *2009-09-182012-10-24Paion英国有限公司Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process
CN102964349A *2011-08-312013-03-13江苏恒瑞医药股份有限公司Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
Patent ID

Patent Title

Submitted Date

Granted Date

Patent ID

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US7435730 Short-acting benzodiazepines
US7528127 Short-acting benzodiazepines
Patent ID

Patent Title

Submitted Date

Granted Date

US7485635 Short-acting benzodiazepines
Patent ID

Patent Title

Submitted Date

Granted Date

US7473689 Short-acting benzodiazepines
US7160880 Short-acting benzodiazepines
CAS Number
PubChem CID
Chemical and physical data
Formula C21H19BrN4O2
Molar mass 439.304 g/mol
3D model (JSmol)

//////////////CNS-7056 , CNS-7056X , ONO-2745  , CNS 7056 , CNS 7056X , ONO 2745, REMIMAZOLAM, PHASE 3, PHASE 3, PAION, Anesthesia, 308242-62-8


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