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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , 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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Zanubrutinib, ザヌブルチニブ , занубрутиниб , زانوبروتينيب ,


Zanubrutinib (USAN/INN).png

Image result for Zanubrutinib

ChemSpider 2D Image | zanubrutinib | C27H29N5O3

Zanubrutinib, BGB-3111

Formula
C27H29N5O3
CAS
1691249-45-2
Mol weight
471.5509

FDA , 2019/11/14, Brukinsa

ザヌブルチニブ ,

занубрутиниб [Russian]
زانوبروتينيب [Arabic]
(7S)-7-(1-Acryloyl-4-piperidinyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
Pyrazolo[1,5-a]pyrimidine-3-carboxamide, 4,5,6,7-tetrahydro-7-[1-(1-oxo-2-propen-1-yl)-4-piperidinyl]-2-(4-phenoxyphenyl)-, (7S)-

Antineoplastic, Bruton’s tyrosine kinase inhibitor, Mantle cell lymphoma

Zanubrutinib, sold under the brand name Brukinsa, is for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.[3]

It was approved for medical use in the United States in November 2019.[4][3][5][6]

Zanubrutinib is classified as a Bruton’s tyrosine kinase (BTK) inhibitor. It is administered orally.

History

Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase II open-label, multicenter, single-arm trial of 86 patients with mantle cell lymphoma (MCL) who received at least one prior therapy.[5] Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity.[5] Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B‑cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.[5][6]

The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee.[5] In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84% (95% CI: 74, 91), with a complete response rate of 59% (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable).[5] In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84% (95% CI: 67, 95), with a complete response rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).[5] Trial 1 was conducted at 13 sites in China, and Trial 2 was conducted at 25 sites in the United States, United Kingdom, Australia, New Zealand, Italy, and South Korea.[6]

The U.S. Food and Drug Administration (FDA) granted zanubrutinib priority reviewaccelerated approvalbreakthrough therapydesignation, and orphan drug designation.[3][5][7]

The FDA approved zanubrutinib in November 2019, and granted the application for Brukinsa to BeiGene USA Inc.[3][5][8]

PAPER

https://www.x-mol.com/paper/5799457

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase Journal of Medicinal Chemistry ( IF 6.054 ) Pub Date: 2019-08-19 , DOI: 10.1021 / acs.jmedchem.9b00687

Yunhang Guo, Ye Liu, Nan Hu, Desheng Yu, Changyou Zhou, Gongyin Shi, Bo Zhang, Min Wei, Junhua Liu, Lusong Luo, Zhiyu Tang, Huipeng Song, Yin Guo, Xuesong Liu, Dan Su, Shuo Zhang, Xiaomin Song , Xing Zhou, Yuan Hong, Shuaishuai Chen, Zhenzhen Cheng, Steve Young, Qiang Wei, Haisheng Wang, Qiuwen Wang, Lei Lv, Fan Wang, Haipeng Xu, Hanzi Sun, Haimei Xing, Na Li, Wei Zhang, Zhongbo Wang, Guodong Liu, Zhijian Sun, Dongping Zhou, Wei Li, Libin Liu, Lai Wang, Zhiwei Wang

Aberrant activation of Bruton’s tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
PATENT
WO 2014173289
WO 2018033135
PATENT
WO 2018033853

Bruton’s tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. Btk plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated by upstream Src-family kinases. Once activated, Btk in turn phosphorylates PLC gamma, leading to effects on B-cell function and survival (Humphries et al., J. Biol.Chem. 279: 37651, 2004).

[0003] These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk cause an inherited B-cell specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling may result in dysregulated B-cell activation leading to a number of autoimmune and inflammatory diseases. Preclinical studies show that Btk deficient mice are resistant to developing collagen- induced arthritis. Moreover, clinical studies of Rituxan, a CD20 antibody to deplete mature B-cells, reveal the key role of B-cells in a number of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis (Gurcan et al, Int. Immunopharmacol. 9: 10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and/or inflammatory diseases.

[0004] In addition, aberrant activation of Btk plays an important role in pathogenesis of B-cell lymphomas indicating that inhibition of Btk is useful in the treatment of hematological malignancies (Davis et al, Nature 463: 88-92, 2010). Preliminary clinical trial results showed that the Btk inhibitor PCI-32765 was effective in treatment of several types of B-cell lymphoma (for example, 54thAmerican Society of Hematology (ASH) annual meeting abstract, Dec. 2012: 686 The Bruton’s Tyrosine Kinase (Btk) Inhibitor, Ibrutinib (PCI- 32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multic enter, Open-Label, Phase I Study). Because Btk plays a central role as a mediator in multiple signal transduction pathways, inhibitors of Btk are of great interest as anti-inflammatory and/or anti-cancer agents {Mohamed et al., Immunol. Rev. 228: 58-73, 2009; Pan, Drug News perspect 21: 357-362, 200%; Rokosz et al., Expert Opin. Ther. Targets 12: 883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7: 624-632, 2007; Lou et al, J. Med. Chem. 55(10): 4539-4550, 2012).

[0005] International application WO2014173289A disclosed a series of fused heterocyclic compounds as Btk inhibitors. In particular, WO2014173289A disclosed

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimi dine-3-carboxamide (hereinafter C

Compound 1

[0006] Compound 1 is a potent, specific and irreversible BTK kinase inhibitor. The data generated in preclinical studies using biochemical, cell based and animal studies suggested that Compound 1 could offer significant benefit in inhibiting tumor growth in B-cell malignancies. As Compound 1 was shown to be more selective than ibrutinib for inhibition of BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC, it is expected to give rise to less side-effects than ibrutinib in clinic. In addition, Compound 1 showed significantly less inhibition of rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) than ibrutinib due to weaker ITK inhibition, and therefore may provide better efficacy when combined with rituximab or other ADCC-dependent antibody in treating B-cell malignancies.

[0007] Preclinical safety evaluation has demonstrated that Compound 1 was safer than ibrutinib in terms of the overall tolerance and severe toxicities in both rat and dog single and repeat dose toxicity studies up to 28 days. Additionally, Compound 1 had better bioavailability without accumulation issues observed for ibrutinib. These unique characteristics warrant further evaluation of Compound 1 in clinical studies.

[0008] However, Compound 1 was found to be an amorphous form according to the preparation method for Compound 27 in WO 2014173289A, which was further confirmed by the X-Ray Powder Diffraction pattern of FIG. 7A. The amorphous form was shown to have a low glass transition temperature as shown in FIG. 7B, indicating some difficulties in the drug formulation with the amorphous form, such as low stability and hard to purify. Therefore, it’s necessary to develop a new form of Compound 1 which possesses characteristics such as high melting point and better stability, suitable for drug formulation.

Scheme 1: Preparation of Compound 1 and deuterium-labeled Compound 1

Deuterium-Labeled Compound 1

Step 15: Synthesis of

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolori,5-a1pyrimi dine-3-carboxamide (Compound 1

[0105] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHC03 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and

stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0106] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)

-4,5,6,7-tetrahydropyrazolori,5-a1pyrimidine-3-carboxamide (Compound 1, alternative method)

[0107] A mixture of CHsCN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCCb (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3%> w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

Step 16: Preparation of Crystalline Form A of Compound 1

[0108] The above cake of Compound 1 was dissolved in 7.0 volumes of DCM, and then swapped to solvent EA. After recrystallization from EA/MTBE, the cakes was collected by centrifugation, and was dried under vacuum. This gave 4.44 Kg product (Yield: 70.2%).

[0109] The product was then characterized by X-ray powder diffraction (XRPD) pattern method, which was generated on a PANalytical Empyrean X-ray powder diffractometer with the XRPD parameters as follows: X-Ray wavelength (Cu, ka, Kal (A): 1.540598, Ka2(A): 1.544426; Ka2/Kal intensity ratio: 0.50); X-Ray tube setting (45 Kv, 40mA); divergence slit (automatic); scan mode (Continuous); scan range (°2TH) (3°-40); step size (°2TH) (0.0131); scan speed (°/min) (about 10). The XRPD result found the resultant product as a crystalline shown in FIG. 1.

[0110] The differential scanning calorimetry (DSC) curves shown as in FIG. 2 was generated on a TA Q2000 DSC from TA Instruments. The DSC parameters used includes: temperature (25°C-desired temperature); heating rate (10°C/min) ; method (ramp); sample pan (aluminum, crimped); purge gas (N2). DSC result showed a sharp melting point at 139.4°C (onset temperature).

[0111] The thermo-gravimetric analysis (TGA) curves shown as in FIG. 3 was generated on a TA Q5000 TGA from TA Instruments. The TGA parameters used includes: temperature

(RT-desired temperature); heating rate (10°C/min); method (ramp); sample pan (platinum, open); purge gas (N2). TGA result showed is anhydrous with no weight loss even up to 110 °C.

[0112] The proton nuclear magnetic resonance ^H-NMR) shown as in FIG. 4 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. ¾-NMR (DMSO-de) δ 7.50 (d, J= 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J= 7.6 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.85-6.72 (m, 1H), 6.67 (s, 1H), 6.07 (dd, J= 16.8, 2.2 Hz, 1H), 5.64 (dd, J= 10.4 Hz, 2.2 Hz, 1H), 4.55-4.38 (m, 1H), 4.17-3.94 (m, 2H), 3.33-3.22 (m, 2H), 3.08-2.88 (m, 1H), 2.67-2.51 (m, 1H), 2.36-2.15 (m, 1H), 2.12-1.82 (m, 2H), 1.79-1.65 (m, 1H), 1.63-1.49 (m, 1H), 1.38-1.08 (m, 2H).

[0113] The carbon nuclear magnetic resonance (13C-NMR) shown as in FIG. 5 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. 13C-NMR spectra for Crystalline Form A of Compound 1.

PATENT
 WO 2019108795

Step 15: Synthesis of (S)-7-(1-acrvlovlpiperidin-4-vl)-2-(4-phenoxvphenyl)-4.5.6.7-tetrahvdropvrazolo[1.5-a1pvrimidine-3-carboxamide (Compound 1)

[0119] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHCO3 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0120] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl) -4.5.6.7-tetrahvdropvrazolori.5-a1pvrimidine-3-carboxamide (Compound 1. alternative method)

[0121] A mixture of CH3CN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCO3 (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3% w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

References

  1. ^ “Zanubrutinib (Brukinsa) Use During Pregnancy”Drugs.com. 3 January 2020. Retrieved 26 January 2020.
  2. ^ “Zanubrutinib”DrugBank. Retrieved 15 November 2019.
  3. Jump up to:a b c d “FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage”U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019.  This article incorporates text from this source, which is in the public domain.
  4. ^ “Brukinsa (zanubrutinib) FDA Approval History”Drugs.com. 14 November 2019. Archived from the original on 15 November 2019. Retrieved 15 November 2019.
  5. Jump up to:a b c d e f g h i “FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma”U.S. Food and Drug Administration (FDA)(Press release). 15 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019.  This article incorporates text from this source, which is in the public domain.
  6. Jump up to:a b c “Drug Trials Snapshots Brukinsa”U.S. Food and Drug Administration (FDA). 14 November 2019. Retrieved 26 January 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ “Zanubrutinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 28 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019.  This article incorporates text from this source, which is in the public domain.
  8. ^ “Drug Approval Package: Brukinsa”U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.

External links

Zanubrutinib
Zanubrutinib.svg
Clinical data
Trade names Brukinsa
Other names BGB-3111
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: N (Not classified yet) [1]
Routes of
administration
By mouth
Drug class Bruton’s tyrosine kinase(BTK) inhibitor
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
PubChem SID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C27H29N5O3
Molar mass 471.5509 g·mol−1
3D model (JSmol)

/////////////////Zanubrutinib, FDA 2019, ザヌブルチニブ , занубрутиниб زانوبروتينيب BGB-3111

Brilliant blue G , ブリリアントブルーG ,


Brilliant Blue G.png

2D chemical structure of 6104-58-1

Brilliant blue G

FDA 2019, 12/20/2019, TISSUEBLUE, New Drug Application (NDA): 209569
Company: DUTCH OPHTHALMIC, PRIORITY; Orphan

OPQ recommends APPROVAL of NDA 209569 for commercialization of TissueBlue (Brilliant Blue G Ophthalmic Solution), 0.025%

Neuroprotectant

sodium;3-[[4-[[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate

Formula
C47H48N3O7S2. Na
CAS
6104-58-1
Mol weight
854.0197

ブリリアントブルーG, C.I. Acid Blue 90

UNII-M1ZRX790SI

M1ZRX790SI

6104-58-1

Brilliant Blue G

Derma Cyanine G

SYN

////////////Brilliant blue G , ブリリアントブルーG , C.I. Acid Blue 90, FDA 2019, PRIORITY,  Orphan

CCN(CC1=CC(=CC=C1)S(=O)(=O)[O-])C2=CC(=C(C=C2)C(=C3C=CC(=[N+](CC)CC4=CC(=CC=C4)S(=O)(=O)[O-])C=C3C)C5=CC=C(C=C5)NC6=CC=C(C=C6)OCC)C.[Na+]

  • Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, hydroxide, inner salt, monosodium salt
  • Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, inner salt, monosodium salt (9CI)
  • Brilliant Indocyanine G (6CI)
  • C.I. Acid Blue 90 (7CI)
  • C.I. Acid Blue 90, monosodium salt (8CI)
  • Acid Blue 90
  • Acid Blue G 4061
  • Acid Blue PG
  • Acid Bright Blue G
  • Acid Brilliant Blue G
  • Acid Brilliant Cyanine G
  • Acidine Sky Blue G
  • Amacid Brilliant Cyanine G
  • Anadurm Cyanine A-G
  • BBG
  • Benzyl Cyanine G
  • Biosafe Coomassie Stain
  • Boomassie blue silver
  • Brilliant Acid Blue G
  • Brilliant Acid Blue GI
  • Brilliant Acid Blue J
  • Brilliant Acid Cyanine G
  • Brilliant Blue G
  • Brilliant Blue G 250
  • Brilliant Blue J
  • Brilliant Indocyanine GA-CF
  • Bucacid Brilliant Indocyanine G
  • C.I. 42655
  • CBB-G 250
  • Colocid Brilliant Blue EG
  • Coomassie Blue G
  • Coomassie Blue G 250
  • Coomassie Brilliant Blue G
  • Coomassie Brilliant Blue G 250
  • Coomassie G 250
  • Cyanine G
  • Daiwa Acid Blue 300
  • Derma Cyanine G
  • Derma Cyanine GN 360
  • Dycosweak Acid Brilliant Blue G
  • Eriosin Brilliant Cyanine G
  • Fenazo Blue XXFG
  • Impero Azure G
  • Kayanol Cyanine G
  • Lerui Acid Brilliant Blue G
  • Milling Brilliant Blue 2J
  • NSC 328382
  • Optanol Cyanine G
  • Orient Water Blue 105
  • Orient Water Blue 105S
  • Polar Blue G
  • Polar Blue G 01
  • Polycor Blue G
  • Sandolan Cyanine N-G
  • Sellaset Blue B
  • Serva Blue G
  • Serva Blue G 250
  • Silk Fast Cyanine G
  • Simacid Blue G 350
  • Sumitomo Brilliant Indocyanine G
  • Supranol Cyanin G
  • Supranol Cyanine G
  • TissueBlue
  • Triacid Fast Cyanine G
  • Water Blue 105
  • Water Blue 105S
  • Water Blue 150
  • Xylene Brilliant Cyanine G

Fluorodopa F 18, フルオロドパ (18F), флуородопа (18F) , فلورودوبا (18F) , 氟[18F]多巴 ,


92812-82-3.png

ChemSpider 2D Image | Fluorodopa F 18 | C9H1018FNO4

Fluorodopa F 18

2019/10/10, fda 2019,

Formula
C9H10FNO4
Cas
92812-82-3
Mol weight
215.1784

Diagnostic aid (brain imaging), Radioactive agent, for use in positron emission tomography (PET)

CAS 92812-82-3

フルオロドパ (18F)

L-6-(18F)Fluoro-DOPA
L-Tyrosine, 2-fluoro-18F-5-hydroxy- [ACD/Index Name]
флуородопа (18F) [Russian] [INN]
فلورودوبا (18F) [Arabic] [INN]
氟[18F]多巴 [Chinese] [INN]
((18)F)FDOPA
2-(fluoro-(18)F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-L-DOPA
2C598205QX
6-((18)F)fluoro-L-DOPA
6-(18F)Fluoro-L-DOPA
6692
(18F)FDOPA
2-((18)F)fluoro-5-hydroxy-L-tyrosine

Fluorodopa, also known as FDOPA, is a fluorinated form of L-DOPA primarily synthesized as its fluorine-18isotopologue for use as a radiotracer in positron emission tomography (PET).[1] Fluorodopa PET scanning is a valid method for assessing the functional state of the nigrostriatal dopaminergic pathway. It is particularly useful for studies requiring repeated measures such as examinations of the course of a disease and the effect of treatment

In October 2019, Fluorodopa was approved in the United States for the visual detection of certain nerve cells in adult patients with suspected Parkinsonian Syndromes (PS).[2][3]

The U.S. Food and Drug Administration (FDA) approved Fluorodopa F 18 based on evidence from one clinical trial of 56 patients with suspected PS.[2] The trial was conducted at one clinical site in the United States.[2]

PAPER

 Organic & Biomolecular Chemistry (2019), 17(38), 8701-8705

A one-pot two-step synthesis of 6-[18F]fluoro-L-DOPA ([18F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [18F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol−1), n = 3, and has been validated to produce the radiotracer for human use.

Graphical abstract: One-pot synthesis of high molar activity 6-[18F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor
Radiosynthesis of [ 18F]6F-l-DOPA The synthesis of [ 18F]6F-l-DOPA was fully-automated using a General Electric (GE) TRACERLab FXFN synthesis module (Figure S1) loaded as follows: V1: 500 µL 15mg/mL TBAOTf + 0.2 mg/mL Cs2CO3 in water; V2: 1000 µL acetonitrile; V3: 4 µmol Bpin precursor, 20 µmol Cu2+ , 500 µmol pyridine in 1 mL DMF; V4: 0.2 mL 0.25 M ascorbic acid + 0.6 mL 12.1 N HCl; V6: 3 mL acetonitrile; V7: 10 mL 0.9% saline, USP; V8: 2 mL ethanol, USP; Dilution flask: 100 mL acetonitrile ; F18 separation port: QMA cartridge ; C18 port: Strata cartridge.

PATENT

KR 2019061368

The present invention relates to an L-dopa precursor compd., a method for producing the same, and a method for producing 18F-labeled L-dopa using the same.  The method of prepg. 18F-labeled L-dopa I using the L-dopa precursor II [A = halogen-(un)substituted alkyl; W, X, Y = independently protecting group] can improve the labeling efficiency of 18F.  After the labeling reaction, sepn. and purifn. steps of the product can be carried out continuously and it can be performed with on-column labeling (a method of labeling through the column).  The final product I, 18 F-labeled L-dopa, can be obtained at a high yield relative to conventional methods.  Further, it has an advantage that it is easy to apply various methods such as bead labeling.

PAPER

Science (Washington, DC, United States) (2019), 364(6446), 1170-1174.

PAPER

European Journal of Organic Chemistry (2018), 2018(48), 7058-7065.

PATENT

WO 2018115353

CN 107311877

References

  1. ^ Deng WP, Wong KA, Kirk KL (June 2002). “Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA”. Tetrahedron: Asymmetry13 (11): 1135–1140. doi:10.1016/S0957-4166(02)00321-X.
  2. Jump up to:a b c “Drug Trials Snapshots: Fluorodopa F 18”U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 27 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
  3. ^ “Drug Approval Package: Fluorodopa F18”U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 27 November 2019. Retrieved 26 November 2019. This article incorporates text from this source, which is in the public domain.
Fluorodopa
Fluorodopa.png
Clinical data
Other names 6-fluoro-L-DOPA, FDOPA
License data
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C9H10FNO4
Molar mass 215.18 g/mol g·mol−1
3D model (JSmol)

//////////////////Fluorodopa F 18, フルオロドパ (18F), FDA 2019, флуородопа (18F) فلورودوبا (18F) 氟[18F]多巴 , radio labelled

N[C@@H](CC1=CC(O)=C(O)C=C1[18F])C(O)=O

Enfortumab vedotin


Image result for enfortumab vedotin

PADCEV™ (enfortumab vedotin-ejfv) Structural Formula - Illustration

Image result for enfortumab vedotin

2D chemical structure of 1346452-25-2

Enfortumab vedotin

Formula
C6642H10284N1742O2063S46
Cas
1346452-25-2
Mol weight
149022.148

AGS-22M6E, enfortumab vedotin-ejfv

Fda approved 2019/12/18, Padcev

Antineoplastic, Nectin-4 antibody, Tubulin polymerization inhibitor, Urothelial cancer

エンホルツマブベドチン (遺伝子組換え);

protein Based Therapies, Monoclonal antibody, mAb, 

UNII DLE8519RWM

Immunoglobulin G1, anti-(human nectin-4) (human monoclonal AGS-22C3 γ1-chain), disulfide with human monoclonal AGS-22C3 κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Other Names

  • AGS 22CE
  • AGS 22M6E
  • AGS 22ME
  • Enfortumab vedotin
  • Enfortumab vedotin-ejfv
  • Immunoglobulin G1 (human monoclonal AGS-22M6 γ1-chain), disulfide with human monoclonal AGS-22M6 κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide
  • Padcev

Protein Sequence

Sequence Length: 1322, 447, 447, 214, 214multichain; modified (modifications unspecified)

Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers.3 It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link.3 It is similar to brentuximab vedotin, another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4.

The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics2 and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.3
The most common side effects for patients taking enfortumab vedotin were fatigue, peripheral neuropathy (nerve damage resulting in tingling or numbness), decreased appetite, rash, alopecia (hair loss), nausea, altered taste, diarrhea, dry eye, pruritis (itching) and dry skin. [4]Enfortumab vedotin[1] (AGS-22M6E) is an antibody-drug conjugate[2] designed for the treatment of cancer expressing Nectin-4.[3]Enfortumab refers to the monoclonal antibody part, and vedotin refers to the payload drug (MMAE) and the linker.

The fully humanized antibody was created by scientists at Agensys (part of Astellas) using Xenomice from Amgen; the linker technology holding the antibody and the toxin together was provided by and licensed from Seattle Genetics.[5]

Results of a phase I clinical trial were reported in 2016.[2]

In December 2019, enfortumab vedotin-ejfv was approved in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.[4]

Enfortumab vedotin was approved based on the results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.[4] The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response.[4] The median duration of response was 7.6 months.[4]

The application for enfortumab vedotin-ejfv was granted accelerated approvalpriority review designation, and breakthrough therapydesignation.[4] The U.S. Food and Drug Administration (FDA) granted the approval of Padcev to Astellas Pharma US Inc.[4]

Indication

Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.3

Associated Conditions

Pharmacodynamics

Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.3 Patients with moderate to severe hepatic impairment should not use enfortumab vedotin – though it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.3 Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.3

Mechanism of action

Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.3 It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein which is highly expressed in urothelial cancers,1 attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.3

PATENT

WO 2016176089

WO 2016138034

WO 2017186928

WO 2017180587

WO 2017200492

US 20170056504

PAPER

Cancer Research (2016), 76(10), 3003-3013.

General References

  1. Hanna KS: Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma. Drugs. 2019 Dec 10. pii: 10.1007/s40265-019-01241-7. doi: 10.1007/s40265-019-01241-7. [PubMed:31823332]
  2. McGregor BA, Sonpavde G: Enfortumab Vedotin, a fully human monoclonal antibody against Nectin 4 conjugated to monomethyl auristatin E for metastatic urothelial Carcinoma. Expert Opin Investig Drugs. 2019 Oct;28(10):821-826. doi: 10.1080/13543784.2019.1667332. Epub 2019 Sep 17. [PubMed:31526130]
  3. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]

References

External links

Enfortumab vedotin
Monoclonal antibody
Type Whole antibody
Source Human
Target Nectin-4
Clinical data
Trade names Padcev
Other names AGS-22M6E, AGS-22CE, enfortumab vedotin-ejfv
License data
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChemSID
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6642H10284N1742O2063S46
Molar mass 149.0 kg/mol g·mol−1

PADCEV™
(enfortumab vedotin-ejfv) for Injection, for Intravenous Use

DESCRIPTION

Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.

Figure 1: Structural Formula

PADCEV™ (enfortumab vedotin-ejfv) Structural Formula - Illustration

Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis.

PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL [see DOSAGE AND ADMINISTRATION]. After reconstitution, each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0.

///////////////Enfortumab vedotin, AGS-22M6E, エンホルツマブベドチン (遺伝子組換え) , protein Based Therapies, Monoclonal antibody, mAb, FDA 2019

[*]SC1CC(=O)N(CCCCCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(=O)N)C(=O)Nc2ccc(COC(=O)N(C)[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@@H](CC(=O)N3CCC[C@H]3[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c4ccccc4)OC)cc2)C1=O

Cefiderocol, セフィデロコル , цефидерокол , سيفيديروكول , 头孢德罗 ,


Cefiderocol.svg

ChemSpider 2D Image | cefiderocol | C30H34ClN7O10S2

Cefiderocol

セフィデロコル;

Formula
C30H34ClN7O10S2
CAS
1225208-94-5
Mol weight
752.2149

Antibacterial, Cell wall biosynthesis inhibitor, enicillin binding protein, Siderophore cephalosporin

Fetroja (TN)

FDA, Cefiderocol, APPROVED, 2019/11/14

(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxy-2-propanyl)oxy]imino}acetyl]amino}-3-[(1-{2-[(2-chloro-3,4-dihydroxybenzoyl)amino]ethyl}-1-pyrrolidiniumyl)methyl]-8-oxo-5-thia-1-azabicycl o[4.2.0]oct-2-ene-2-carboxylate

S-649266,  GSK 2696266D

Cefiderocol, sold under the brand name Fetroja, is an antibiotic used to treat complicated urinary tract infections when no other options are available.[2] It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa.[3][4][5] It is given by injection into a vein.[6]

It is in the cephalosporin family of medications.[2][7] Cefiderocol was approved for medical use in the United States on November 14, 2019.[2][8]

Cefiderocol, also known as S-649266, is a potent siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. S-649266 shows potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. FDA approved this drug in 11/14/2019 To treat patients with complicated urinary tract infections who have limited or no alternative treatment options

Medical uses

Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.[2][7]

Mechanism of action

Its mechanism of entry into bacterial cells is by binding to iron, which is actively transported into the bacterial cells along with the cefiderocol.[6][9][10][11][12] It is in a medication class known as siderophores,[6][7] and was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA).[13] It bypasses the bacterial porin channels by using the bacteria’s own iron-transport system for being transported in.[14]

History

In 2019, cefiderocol was approved in the United States as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.[2][8]

The safety and effectiveness of cefiderocol was demonstrated in a study of 448 patients with cUTIs.[2] Of the patients who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in patients who received an alternative antibiotic.[2] The clinical response rates were similar between the two treatment groups.[2]

Labeling for cefiderocol includes a warning regarding the higher all-cause mortality rate observed in cefiderocol-treated patients compared to those treated with other antibiotics in a trial in critically ill patients with multidrug-resistant Gram-negative bacterial infections.[2] The cause of the increase in mortality has not been established.[2] Some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities.[2] The higher all-cause mortality rate was observed in patients treated for hospital-acquired/ventilator-associated pneumonia (i.e.nosocomial pneumonia), bloodstream infections, or sepsis.[2] The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections.[2]

Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review.[2] The FDA granted approval of Fetroja, on November 14, 2019, to Shionogi & Co., Ltd.[2]

PATENT

WO 2010050468

WO 2016035845

WO 2016035847

PATENT

WO 2017216765,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017216765&tab=PCTDESCRIPTION

Bacterial infections continue to remain one of the major causes contributing towards human diseases. One of the key challenges in treatment of bacterial infections is the ability of bacteria to develop resistance to one or more antibacterial agents over time. Examples of such bacteria that have developed resistance to typical antibacterial agents include: Penicillin-resistant Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillin-resistant Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often tackled by switching to newer antibacterial agents, which can be more expensive and sometimes more toxic. Additionally, this may not be a permanent solution as the bacteria often develop resistance to the newer antibacterial agents as well in due course. In general, bacteria are particularly efficient in developing resistance, because of their ability to multiply very rapidly and pass on the resistance genes as they replicate. Therefore, there is a need for development of newer ways to treat infections that are becoming resistant to known therapies and methods.

Surprisingly, it has been found that the compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, exhibit synergistic antibacterial activity, even against resistant bacterial strains.

Formula (I)

Example 1

Synthesis of Compound of formula (I)

Step-1: Preparation of intermediate (1):

To the clear solution of (Z)-2[(2-tert-butoxycarbonyl amino-thiazol-4-yl)-carboxy-methyleneaminooxy]2-methyl-propionic acid tert-butyl ester (30 gm, 69.93 mmol) in N,N-dimethyl acetamide (300 ml) was charged triethylamine (17.68 ml, 125.87 mmol) under stirring. The reaction mixture was cooled to -15°C. Methane sulfonyl chloride (12.01 gm, 104. 89 mmol) was charged to this cooled reaction mixture via addition funnel while maintaining temperature at about -15°C. The reaction mixture was stirred for 30 minutes at -15°C after the addition. To the reaction mixture was charged (6 ?,75)-4-methoxybenzyl-7-amino-3-chloromethyl-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride salt (28.25 gm, 69.93 mmol) along with N-methyl morpholine (15.5 ml, 139.86 mmol). The reaction mixture was stirred further for 1 hour at -15°C and the reaction progress was monitored using TLC. After completion of reaction, ethyl acetate (1.2 L) was charged followed by IN aqueous hydrochloric acid (1.2 L) under stirring and cooling was removed to warm up reaction mixture to room temperature. Layers were separated and organic layer was washed with saturated aqueous sodium bicarbonate solution (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and was evaporated under vacuum to provide a crude mass. It was purified using silica gel column chromatography (60-120 mesh, 30% ethyl acetate in hexane) to provide 38 gm of intermediate (1).

Analysis:

1H NMR (CDCls) δ ppm: 8.29 (br s, 1H), 8.17 (d, 1H), 7.35 (d, 2H), 7.31 (s, 1H), 6.91 (d, 2H), 6.21 (dd, 1H), 5.23 (dd, 2H), 5.05 (d, 1H), 4.55 (d, 1H), 4.46 (d, 1H), 3.82 (s, 3H), 3.65 (d, 1H), 3.48 (d, 1H), 1.62 (s, 3H), 1.59 (s, 3H), 1.53 (s, 9H), 1.45 (s, 9H).

Step-2: Preparation of intermediate (2):

The solution of intermediate 1 (45 gm, 57.76 mmol) in dichloro methane (450 ml) was cooled to about -40°C and m-chloroperbenzoic acid (18 gm, 57.76 mmol) was added in three lots at -40°C under stirring. The mixture was stirred for 30 minutes and allowed to warm at -20°C. As TLC showed complete conversion, 5% aqueous sodium thiosulfate solution (1.2 L) was added at -15°C under stirring. The mixture was allowed to warm at room temperature and was charged with ethyl acetate (1.5 L) and stirred for 30 minutes and layers were separated. Organic layer was washed with saturated aqueous sodium bicarbonate solution (1 L) followed by brine (500 ml).

Organic layer was dried over sodium sulphate and evaporated under vacuum to provide 46 gm of intermediate (2).

Analysis:

1H NMR (CDC13) δ ppm: 8.48 (br s, 1H), 7.89 (d, 1H), 7.34 (d, 2H), 7.29 (s, 1H), 6.92 (d, 2H), 6.21 (dd, 1H), 5.27 (dd, 2H), 5.04 (br d, 1H), 4.58 (d, 1H), 4.23 (d, 1H), 3.83 (s, 3H), 3.82 (d, 1H), 3.43 (d, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.53 (9H)1.42 (s, 9H).

Step-3: Preparation of intermediate (3):

Part-1: To the clear solution of intermediate 2 (35 gm, 44.02 mmol) in tetrahydrofuran (350 ml) was charged potassium iodide (14.61 gm, 88.05 mmol) under stirring at 25°C. The suspension was stirred for 5 hours at the same temperature and the reaction was monitored using mass spectroscopy. After completion of the reaction ethyl acetate (600 ml) was added to the reaction mixture followed by 5% aqueous sodium thiosulphate (600 ml). The reaction mixture was stirred for 15 minutes and layers were separated. Organic layer was washed with demineralised water (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and evaporated to dryness under vacuum to provide 38 gm of corresponding iodo-methyl intermediate.

Part-2: To the iodo-methyl intermediate obtained (37.24 gm, 41.98 mmol) in N,N-dimethylformamide (35 ml) was added 2-chloro-3,4-di-(4-methoxybenzyloxy)-N-(pyrrolidin-l-ylethyl)-benzamide (22 gm, 42.98 mmol). The thick mass was stirred at 25°C for 15 hours and the reaction was monitored using mass spectroscopy. Potassium iodide (48.78 gm, 293.8 mmol) was charged to the reaction mass under stirring at 25 °C. The reaction mixture was cooled to -40°C and acetyl chloride (12 ml, 167.9 mmol) was added. After completion of the reaction ethyl acetate (1.2 L) followed by demineralised water (1.2 L) was added to the reaction mass at 0°C. Layers were separated and organic layer was washed with demineralised water (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and was evaporated to dryness under vacuum to obtain quaternary intermediate (3) as iodide salt.

Step-4: Preparation compound of Formula (I):

Compound (3) (30 gm, 21.5 mmol) was dissolved in dichloro methane (300 ml) and anisole (30 gm, mmol) was added under stirring at 25°C. The mixture was cooled to -40° C and 2M aluminium chloride solution in nitromethane (150 ml) was added over 45 minutes at -40°C. As addition was completed reaction mixture was stirred for 1 hour at 0°C. To the reaction mixture 2M aqueous hydrochloric acid (750 ml) and acetonitrile (750 ml) were added and the stirring was

continued for 15 minutes. Di-isopropyl ether (1.5 L) was charged to the reaction mixture and the reaction mass was stirred for 15 minutes at 25°C, and the layers were separated. Aqueous layer was washed with additional di-isopropyl ether (500 ml). HP-21 resin (150 gm) was charged to the aqueous layer. The aqueous layer along with resin was loaded on a resin HP-21 column. The column was eluted with demineralised water till pH of eluent became neutral. Then the column was eluted with 10% acetonitrile in water mixture. Finally the column was eluted with 20% acetonitrile in water mixture. Evaporation of required fractions below 40°C under vacuum provided 5.5 gm of crude compound (I). The crude compound (I) was purified by dissolving in acetonitrile (200 ml) and demineralised water (200 ml) mixture followed by addition of HP-21 resin (200 gm).The slurry thus obtained was loaded on HP-21 resin column. The column was eluted first with demineralised water (3 L) followed by 10% acetonitrile in water mixture (2 L) then followed by 20% acetonitrile in water mixture till complete pure compound from the column is eluted. Pure fractions were collected and lyophilized under vacuum to provide titled compound (I) in pure form.

Analysis:

1H NMR (DMSO d6) δ ppm: 12.5 (br s, 2H), 9.42 (br s, 1H), 8.41 (br t, 1H), 7.28 (br s, 3H), 6.78 (s, 2H), 6.73 (s, 1H), 5.73 (dd, 1H), 5.15 (d, 1H), 5.08 (br d, 1H), 3.71-3.91 (m, 4H), 3.21-3.60 (m, 7H), 1.95-2.19 (m, 4H)1.76 (s, 3H), 1.44 (s, 3H).

HPLC purity: 90.80%

PATENT

WO 2019093450

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019093450&tab=FULLTEXT&_cid=P21-K4M68M-79012-1

To date, various β-lactam antibacterial drugs have been developed and have become one of the clinically important therapeutic agents for bacterial infections. On the other hand, gram-negative bacteria that have acquired resistance to β-lactam antimicrobial agents by producing β-lactamase that degrades β-lactam antimicrobial agents are increasing. According to the molecular classification method of Ambler, β-lactamases are roughly classified into four classes. That is, class A (TEM type, SHV type, CTX-M type, KPC type, etc.), class B (NDM type, IMP type, VIM type, L-1 type, etc.), class C (AmpC type, CMY type, ADC) Type) and class D (such as OXA type). Of these, classes A, C, and D are broadly classified into serine-type β-lactamases, while class B types are classified into metallo-type β-lactamases, each of which can hydrolyze β-lactam antibacterial drugs by different mechanisms. It is known (Non-Patent Document 1).
To date, several β-lactamase inhibitors have been developed to help improve the efficacy of β-lactam antimicrobial agents. However, clavulanic acid, tazobactam, and sulbactam, the most common serine-type β-lactamase inhibitors currently used in the clinic, have inhibitory activity only against specific enzymes belonging to class A. And their usefulness is limited. Avibactam mainly inhibits class A and C enzymes including Klebsiella pneumoniae carbapenemase (KPC) (Non-patent document 2), which is currently a clinical problem. Avibactam is clinically used as a combination drug (AVYCAZ) with ceftazidime, a cephem antibacterial agent, but reports a strain that has acquired resistance in some Klebsiella pneumoniae that produces KPC, a class A enzyme. (Non-Patent Document 3). It also has limited efficacy against class D enzymes. To combat severe β-lactam resistance in the future, it will broadly and potently inhibit class A, C, and D serine β-lactamases, alone or in combination with various β-lactam antibacterials, Serine-type β-lactamase inhibitor that is effective not only against existing β-lactam antibacterial drugs but also against gram-negative bacteria that are resistant to the combination of existing β-lactam antibacterial drugs / β-lactamase inhibitors Drugs are eagerly needed.

Prior art documents

Non-patent literature

[0004]
Non-Patent Document 1: Antimicrobial Agents and Chemotherapy, 54 (3), 969-976,2010
Non-patent Document 2: The Lancet Infrction diseases, 13 (9), 785-796,2013
Non-patent Document 3: Antimicrobial Agents and Chemotherapy, 61 (3), 1-11, 2017

PAPER

 European Journal of Medicinal Chemistry (2018), 155, 847-868

References

  1. ^ Katsube, T.; Echols, R.; Arjona Ferreira, J. C.; et al. (2017). “Cefiderocol, a Siderophore Cephalosporin for Gram‐Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment”Journal of Clinical Pharmacology57 (5): 584–591. doi:10.1002/jcph.841PMC 5412848PMID 27874971.
  2. Jump up to:a b c d e f g h i j k l m n o “FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance”U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Archived from the original on 16 November 2019. Retrieved 15 November 2019. This article incorporates text from this source, which is in the public domain.
  3. ^ Choi, Justin J; McCarthy, Matthew W. (24 January 2018). “Cefiderocol: a novel siderophore cephalosporin”. Expert Opinion on Investigational Drugs27 (2): 193–197. doi:10.1080/13543784.2018.1426745PMID 29318906.
  4. ^ Aoki, Toshiaki; Yoshizawa, Hidenori; Yamawaki, Kenji; et al. (15 July 2018). “Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship”. European Journal of Medicinal Chemistry155: 847–868. doi:10.1016/j.ejmech.2018.06.014ISSN 1768-3254PMID 29960205.
  5. ^ Portsmouth, Simon; van Veenhuyzen, David; Echols, Roger; et al. (25 October 2018). “Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial”The Lancet Infectious Diseases0 (12): 1319–1328. doi:10.1016/S1473-3099(18)30554-1ISSN 1473-3099PMID 30509675.
  6. Jump up to:a b c “Fetroja (cefiderocol) for injection, for intravenous use full prescribing information”(PDF). November 2019. Retrieved 17 November 2019. This article incorporates text from this source, which is in the public domain.
  7. Jump up to:a b c Zhanel GG, Golden AR, Zelenitsky S, et al. (February 2019). “Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli”. Drugs79 (3): 271–289. doi:10.1007/s40265-019-1055-2PMID 30712199.
  8. Jump up to:a b “Cefiderocol New Drug Application”U.S. Food and Drug Administration (FDA)Archived from the original on 4 December 2019. Retrieved 22 November 2019. This article incorporates text from this source, which is in the public domain.
  9. ^ Sato T, Yamawaki K (November 2019). “Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin”Clin. Infect. Dis69 (Supplement_7): S538–S543. doi:10.1093/cid/ciz826PMC 6853759PMID 31724047.
  10. ^ Matthews-King A (26 October 2018). “Antibiotic ‘Trojan horse’ could defeat superbugs causing global medical crisis, trial finds”The Independent. Retrieved 26 October 2018.
  11. ^ Newey S (26 October 2018). “New ‘Trojan horse’ drug proves effective against antibiotic resistant bacteria”The TelegraphISSN 0307-1235. Retrieved 26 October 2018.
  12. ^ Simpson DH, Scott P (2017). “Antimicrobial Metallodrugs”. In Lo K (ed.). Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells. Elsevier. ISBN 9780128038871.
  13. ^ Saisho, Yutaka; Katsube, Takayuki; White, Scott; et al. (March 2018). “Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects” (PDF)Antimicrobial Agents and Chemotherapy62 (3): 1–12. doi:10.1128/AAC.02163-17PMC 5826143PMID 29311072. Retrieved 22 November 2019.
  14. ^ Ito A, Nishikawa T, Matsumoto S, et al. (December 2016). “Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa”Antimicrobial Agents and Chemotherapy60 (12): 7396–7401. doi:10.1128/AAC.01405-16PMC 5119021PMID 27736756.

External links

ADDITIONAL INFORMATION

S-649266 shows potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. MIC90s of S-649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively.

REFERENCES

1: Yamano Y. In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S544-S551. doi: 10.1093/cid/ciz827. PubMed PMID: 31724049; PubMed Central PMCID: PMC6853761.

2: Echols R, Ariyasu M, Nagata TD. Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S559-S564. doi: 10.1093/cid/ciz829. PubMed PMID: 31724048; PubMed Central PMCID: PMC6853756.

3: Sato T, Yamawaki K. Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S538-S543. doi: 10.1093/cid/ciz826. PubMed PMID: 31724047; PubMed Central PMCID: PMC6853759.

4: Bonomo RA. Cefiderocol: A Novel Siderophore Cephalosporin Defeating Carbapenem-resistant Pathogens. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S519-S520. doi: 10.1093/cid/ciz823. PubMed PMID: 31724046; PubMed Central PMCID: PMC6853757.

5: Katsube T, Echols R, Wajima T. Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S552-S558. doi: 10.1093/cid/ciz828. PubMed PMID: 31724042; PubMed Central PMCID: PMC6853762.

6: Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of Humanized Cefiderocol Exposure is Unaltered by Host Iron Overload in the Thigh Infection Model. Antimicrob Agents Chemother. 2019 Oct 28. pii: AAC.01767-19. doi: 10.1128/AAC.01767-19. [Epub ahead of print] PubMed PMID: 31658966.

7: Chen IH, Kidd JM, Abdelraouf K, Nicolau DP. Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model. Antimicrob Agents Chemother. 2019 Oct 7. pii: AAC.01558-19. doi: 10.1128/AAC.01558-19. [Epub ahead of print] PubMed PMID: 31591126.

8: Stevens RW, Clancy M. Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug-Resistant Pseudomonas aeruginosa: A Case Report. Pharmacotherapy. 2019 Nov;39(11):1113-1118. doi: 10.1002/phar.2334. Epub 2019 Oct 22. PubMed PMID: 31550054.

9: Sanabria C, Migoya E, Mason JW, Stanworth SH, Katsube T, Machida M, Narukawa Y, Den Nagata T. Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects. Clin Ther. 2019 Sep;41(9):1724-1736.e4. doi: 10.1016/j.clinthera.2019.07.006. Epub 2019 Aug 1. PubMed PMID: 31378318.

10: Trecarichi EM, Quirino A, Scaglione V, Longhini F, Garofalo E, Bruni A, Biamonte E, Lionello R, Serapide F, Mazzitelli M, Marascio N, Matera G, Liberto MC, Navalesi P, Torti C; IMAGES Group . Successful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report. J Antimicrob Chemother. 2019 Nov 1;74(11):3399-3401. doi: 10.1093/jac/dkz318. PubMed PMID: 31369095.

11: Nakamura R, Ito-Horiyama T, Takemura M, Toba S, Matsumoto S, Ikehara T, Tsuji M, Sato T, Yamano Y. In Vivo Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models. Antimicrob Agents Chemother. 2019 Aug 23;63(9). pii: e02031-18. doi: 10.1128/AAC.02031-18. Print 2019 Sep. PubMed PMID: 31262762; PubMed Central PMCID: PMC6709502.

12: Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019 Jul 1;74(7):1971-1974. doi: 10.1093/jac/dkz123. PubMed PMID: 31220260; PubMed Central PMCID: PMC6587409.

13: Jean SS, Hsueh SC, Lee WS, Hsueh PR. Cefiderocol: a promising antibiotic against multidrug-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther. 2019 May;17(5):307-309. doi: 10.1080/14787210.2019.1612240. Epub 2019 May 6. PubMed PMID: 31055983.

14: Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-Hinton broth. Diagn Microbiol Infect Dis. 2019 Aug;94(4):321-325. doi: 10.1016/j.diagmicrobio.2019.03.003. Epub 2019 Mar 23. PubMed PMID: 31029489.

15: Miyazaki S, Katsube T, Shen H, Tomek C, Narukawa Y. Metabolism, Excretion, and Pharmacokinetics of [(14) C]-Cefiderocol (S-649266), a Siderophore Cephalosporin, in Healthy Subjects Following Intravenous Administration. J Clin Pharmacol. 2019 Jul;59(7):958-967. doi: 10.1002/jcph.1386. Epub 2019 Feb 7. PubMed PMID: 30730562; PubMed Central PMCID: PMC6593826.

16: Zhanel GG, Golden AR, Zelenitsky S, Wiebe K, Lawrence CK, Adam HJ, Idowu T, Domalaon R, Schweizer F, Zhanel MA, Lagacé-Wiens PRS, Walkty AJ, Noreddin A, Lynch Iii JP, Karlowsky JA. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 2019 Feb;79(3):271-289. doi: 10.1007/s40265-019-1055-2. Review. PubMed PMID: 30712199.

17: Huttner A. Cefiderocol for treatment of complicated urinary tract infections – Author’s reply. Lancet Infect Dis. 2019 Jan;19(1):24-25. doi: 10.1016/S1473-3099(18)30728-X. PubMed PMID: 30587291.

18: Portsmouth S, Echols R, Den Nagata T. Cefiderocol for treatment of complicated urinary tract infections. Lancet Infect Dis. 2019 Jan;19(1):23-24. doi: 10.1016/S1473-3099(18)30721-7. PubMed PMID: 30587290.

19: Wagenlehner FME, Naber KG. Cefiderocol for treatment of complicated urinary tract infections. Lancet Infect Dis. 2019 Jan;19(1):22-23. doi: 10.1016/S1473-3099(18)30722-9. PubMed PMID: 30587289.

20: Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, Tenke P, Nagata TD. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1. Epub 2018 Oct 25. PubMed PMID: 30509675.

Cefiderocol
Cefiderocol.svg
Clinical data
Trade names Fetroja
Routes of
administration
Intravenous infusion
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Protein binding 56–58%[1]
Elimination half-life 2.8 hours
Excretion mainly renal (60–70% unchanged)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C30H34ClN7O10S2
Molar mass 752.21 g·mol−1
3D model (JSmol)

////////////Cefiderocol, セフィデロコル , FDA 2019, цефидерокол سيفيديروكول 头孢德罗 , S-649266,  GSK 2696266D

Givosiran, ギボシラン ,


Givosiran.png

File:Givosiran.svg

GIVLAARI (givosiran)) Structural Formula - Illustration

Картинки по запросу Givosiran

2D chemical structure of 1639325-43-1

Givosiran

N-[1,3-bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]-12-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-12-oxododecanamide

Treatment of Acute Hepatic Porphyria (AHP)

Formula
C524H694F16N173O316P43S6
CAS
 1639325-43-1
Mol weight
16300.3229

Treatment of acute hepatic porphyria, RNA interference (RNAi) drug

FDA APPROVED, Givlaari, 2019/11/20

ギボシラン;

RNA, (Cm-sp-Am-sp-Gm-Am-Am-Am-(2′-deoxy-2′-fluoro)G-Am-(2′-deoxy-2′-fluoro)G-Um-(2′-deoxy-2′-fluoro)G-Um-(2′-deoxy-2′-fluoro)C-Um-(2′-deoxy-2′-fluoro)C-Am-Um-Cm-Um-Um-Am), 3′-[[(2S,4R)-1-[29-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[3-[[5-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-1-oxopentyl]amino]propyl]amino]-3-oxopropoxy]methyl]-1,12,19,25-tetraoxo-16-oxa-13,20,24-triazanonacos-1-yl]-4-hydroxy-2-pyrrolidinyl]methyl hydrogen phosphate], complex with RNA (Um-sp-(2′-deoxy-2′-fluoro)A-sp-(2′-deoxy-2′-fluoro)A-(2′-deoxy-2′-fluoro)G-Am-(2′-deoxy-2′-fluoro)U-Gm-(2′-deoxy-2′-fluoro)A-Gm-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)U-Cm-(2′-deoxy-2′-fluoro)U-Um-(2′-deoxy-2′-fluoro)U-Cm-(2′-deoxy-2′-fluoro)U-Gm-sp-Gm-sp-Um) (1:1)

Givosiran, sold under the brand name Givlaari, is for the treatment of adults with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).[1][2]

History

The U.S. Food and Drug Administration (FDA) granted the application for givosiran breakthrough therapy designation, priority reviewdesignation, and orphan drug designation.[1] The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals.[1]

The full ENVISION results demonstrated a 74 percent mean and 90 percent median reduction in the primary endpoint measure of annualized rate of composite attacks in patients on givosiran relative to placebo during the six-month double-blind period. In addition, givosiran achieved statistically significant positive results for five of nine secondary endpoints, with an overall safety and tolerability profile that the Company believes is encouraging, especially in this high unmet need disease. Adverse events (AEs) were reported in 89.6 percent of givosiran patients and 80.4 percent of placebo patients; serious adverse events (SAEs) were reported in 20.8 percent of givosiran patients and 8.7 percent of placebo patients. Ninety-three of 94 patients, or 99 percent, enrolled in the open-label extension (OLE) period of the study. Based on the ENVISION results, the Company plans to complete its rolling submission of a New Drug Application (NDA) and file a Marketing Authorisation Application (MAA) in mid-2019.

“Given the high unmet need in this disease setting, we are very pleased for the patients and families living with acute hepatic porphyria for whom these results signal hope for a potential new therapeutic option,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “Givosiran substantially reduced the frequency of attacks, providing strong support for a treatment benefit, with a consistent effect across all components of the primary endpoint and all subgroups analyzed. In this disease with high burden and associated comorbidities, we’re encouraged by the overall tolerability profile. We firmly believe givosiran has the potential to be a transformative medicine for patients living with AHP.”

“Currently, there are no approved therapies aimed at preventing the painful, often incapacitating attacks and chronic symptoms associated with AHP,” said Manisha Balwani, M.D., M.S, Associate Professor of the Department of Genetics and Genomic Sciences and Department of Medicine at the Icahn School of Medicine at Mount Sinai and principal investigator of the ENVISION study. “The results from ENVISION are promising and demonstrate a strong treatment effect for givosiran, with reduction of attacks and improvement in patient-reported measures of overall health status and quality of life. Thus, givosiran represents a novel and targeted treatment approach that has the potential to make a significant impact on the lives of patients who are struggling with the disabling symptoms of this disease.”

Efficacy Results

Givosiran met the primary efficacy endpoint with a 74 percent mean reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with acute intermittent porphyria (AIP) over six months (p equal to 6.04×10-9). There was a corresponding 90 percent median reduction in composite annualized attack rate (AAR), with a median AAR of 1.0 in givosiran patients compared with a median AAR of 10.7 in placebo patients. Fifty percent of givosiran-treated patients were attack-free during the six-month treatment period as compared to 16.3 percent of placebo-treated patients. The reductions in attack rates were observed across all components of the primary endpoint. The treatment benefit for givosiran compared to placebo was maintained across all pre-specified patient subgroups, including age, race, geography, historical attack rates, prior hemin prophylaxis status, disease severity, and other baseline characteristics.

Givosiran also demonstrated statistically significant differences in five of nine hierarchically tested secondary endpoints relative to placebo. These included mean reductions of:

  • 91 percent in urinary aminolevulinic acid (ALA) in patients with AIP at three months (p equal to 8.74×10-14).
  • 83 percent in urinary ALA in patients with AIP at six months (p equal to 6.24×10-7).
  • 73 percent in urinary levels of porphobilinogen (PBG) in patients with AIP at six months (p equal to 8.80×10-7).
  • 77 percent in the number of annualized days on hemin in patients with AIP (p equal to 2.35×10-5).
  • 73 percent in composite AAR for patients with any AHP (p equal to 1.35×10-8).

The remaining four secondary endpoints did not meet the prespecified criteria for statistical significance in hierarchical testing.

Image result for Givosiran

About Acute Hepatic Porphyria

Acute hepatic porphyria (AHP) refers to a family of rare, genetic diseases characterized by potentially life-threatening attacks and for some patients chronic debilitating symptoms that negatively impact daily functioning and quality of life. AHP is comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD-deficiency porphyria (ADP). These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks. Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis, and consequently, patients afflicted by AHP often remain without a proper diagnosis for up to 15 years. In addition, long-term complications of AHP and its treatment can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease, including iron overload, fibrosis, cirrhosis and hepatocellular carcinoma. Currently, there are no treatments approved to prevent debilitating attacks or to treat the chronic manifestations of the disease.

About Givosiran

Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP). Monthly administration of givosiran has the potential to significantly lower induced liver ALAS1 levels in a sustained manner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid (ALA) and porphobilinogen (PBG), to near normal levels. By reducing accumulation of these intermediates, givosiran has the potential to prevent or reduce the occurrence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease. Givosiran utilizes Alnylam’s Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Givosiran has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) and PRIME Designation by the European Medicines Agency (EMA). Givosiran has also been granted Orphan Drug Designations in both the U.S. and the EU for the treatment of AHP. The safety and efficacy of givosiran were evaluated in the ENVISION Phase 3 trial with positive results; these results have not been evaluated by the FDA, the EMA or any other health authority.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

References

  1. Jump up to:a b c “FDA approves first treatment for inherited rare disease”U.S. Food and Drug Administration (FDA) (Press release). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
  2. ^ “FDA approves givosiran for acute hepatic porphyria”U.S. Food and Drug Administration (FDA) (Press release). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
  3. The New England journal of medicine (2019), 380(6), 549-558.
  4. New England Journal of Medicine (2019), 380(6), 549-558.
  5. Toxicologic Pathology (2018), 46(7), 735-745.

External links

  • “Givosiran”Drug Information PortalU.S. National Library of Medicine (NLM).
  • GIVLAARI
    (givosiran) Injection, for Subcutaneous Use

    DESCRIPTION

    GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes.

    The structural formulas of the givosiran drug substance in its sodium form, and the ligand (L96), are presented below.

    GIVLAARI (givosiran)) Structural Formula - Illustration

    Abbreviations: Af = adenine 2′-F ribonucleoside; Cf = cytosine 2′-F ribonucleoside; Uf = uracil 2′-F ribonucleoside; Am = adenine 2′-OMe ribonucleoside; Cm = cytosine 2′-OMe ribonucleoside; Gf = guanine 2′-F ribonucleoside; Gm = guanine 2′-OMe ribonucleoside; Um = uracil 2′-OMe ribonucleoside; L96 = triantennary GalNAc (N-acetylgalactosamine)

    GIVLAARI is supplied as a sterile, preservative-free, 1-mL colorless-to-yellow solution for subcutaneous injection containing 189 mg givosiran in a single-dose, 2-mL Type 1 glass vial with a TEFLON®-coated stopper and a flip-off aluminum seal. GIVLAARI is available in cartons containing one single-dose vial each. Water for injection is the only excipient used in the manufacture of GIVLAARI.

    The molecular formula of givosiran sodium is C524 H651 F16 N173 Na43 O316 P43 S6 with a molecular weight of 17,245.56 Da.

    The molecular formula of givosiran (free acid) is C524 H694 F16 N173 O316 P43 S6 with a molecular weight of 16,300.34 Da.

Givosiran
Clinical data
Trade names Givlaari
Routes of
administration
Subcutaneous injection
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
UNII
KEGG
Chemical and physical data
Formula C524H694F16N173O316P43S6
Molar mass 16300.42 g·mol−1
3D model (JSmol)

/////////Givosiran, ギボシラン , FDA 2019, Acute Hepatic Porphyria,

Golodirsen, ゴロジルセン;


VYONDYS 53 (golodirsen) Structural Formula - Illustration

Golodirsen

  • RNA, [P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(G-m5U-m5U-G-C-C-m5U-C-C-G-G-m5U-m5U-C-m5U-G-A-A-G-G-m5U-G-m5U-m5U-C), 5′-[P-[4-[[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]carbonyl]-1-piperazinyl]-N,N-dimethylphosphonamidate]
  • Nucleic Acid Sequence
  • Sequence Length: 25
Formula
C305H481N138O112P25
CAS
1422959-91-8
Mol weight
8647.2841
  • Exon 53: NG-12-0163
  • Golodirsen
  • SRP 4053

Nucleic Acid Sequence

Sequence Length: 252 a 6 c 8 g 9 umodified

FDA APPROVED, Vyondys 53, 019/12/12

Antisense oligonucleotide

ゴロジルセン;

Duchenne muscular dystrophy (DMD variant amenable to exon 53 skipping)

Image result for Golodirsen

VYONDYS 53 (golodirsen) injection is a sterile, aqueous, preservative-free, concentrated solution for dilution prior to intravenous administration. VYONDYS 53 is a clear to slightly opalescent, colorless liquid. VYONDYS 53 is supplied in single-dose vials containing 100 mg golodirsen (50 mg/mL). VYONDYS 53 is formulated as an isotonic phosphate buffered saline solution with an osmolality of 260 to 320 mOSM and a pH of 7.5. Each milliliter of VYONDYS 53 contains: 50 mg golodirsen; 0.2 mg potassium chloride; 0.2 mg potassium phosphate monobasic; 8 mg sodium chloride; and 1.14 mg sodium phosphate dibasic, anhydrous, in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust pH.

Golodirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Golodirsen contains 25 linked subunits. The sequence of bases from the 5′ end to 3′ end is GTTGCCTCCGGTTCTGAAGGTGTTC. The molecular formula of golodirsen is C305H481N138O112P25 and the molecular weight is 8647.28 daltons. The structure of golodirsen is:

VYONDYS 53 (golodirsen) Structural Formula - Illustration
Side Effects & Drug Interactions

SIDE EFFECTS

  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the VYONDYS 53 clinical development program, 58 patients received at least one intravenous dose of VYONDYS 53, ranging between 4 mg/kg (0.13 times the recommended dosage) and 30 mg/kg (the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 to 13 years. Most (86%) patients were Caucasian.

VYONDYS 53 was studied in 2 double-blind, placebo-controlled studies.

In Study 1 Part 1, patients were randomized to receive once-weekly intravenous infusions of VYONDYS 53 (n=8) in four increasing dose levels from 4 mg/kg to 30 mg/kg or placebo (n=4), for at least 2 weeks at each level. All patients who participated in Study 1 Part 1 (n=12) were continued into Study 1 Part 2, an open-label extension, during which they received VYONDYS 53 at a dose of 30 mg/kg IV once weekly [see Clinical Studies].

In Study 2, patients received VYONDYS 53 (n=33) 30 mg/kg or placebo (n=17) IV once weekly for up to 96 weeks, after which all patients received VYONDYS 53 at a dose of 30 mg/kg.

Adverse reactions observed in at least 20% of treated patients in the placebo-controlled sections of Studies 1 and 2 are shown in Table 1.

Table 1: Adverse Reactions That Occurred in At Least 20% of VYONDYS 53-Treated Patients and at a Rate Greaterthan Placebo in Studies 1 and 2

Adverse Reaction VYONDYS 53
(N = 41) %
Placebo
(N = 21) %
Headache 41 10
Pyrexia 41 14
Fall 29 19
Abdominal pain 27 10
Nasopharyngitis 27 14
Cough 27 19
Vomiting 27 19
Nausea 20 10

Other adverse reactions that occurred at a frequency greater than 5% of VYONDYS 53-treated patients and at a greater frequency than placebo were: administration site pain, back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, tachycardia, catheter site related reaction, constipation, and fracture.

Hypersensitivity reactions have occurred in patients treated with VYONDYS 53 [see WARNINGS AND PRECAUTIONS].

Antisense technology provides a means for modulating the expression of one or more specific gene products, including alternative splice products, and is uniquely useful in a number of therapeutic, diagnostic, and research applications. The principle behind antisense technology is that an antisense compound, e.g., an oligonucleotide, which hybridizes to a target nucleic acid, modulates gene expression activities such as transcription, splicing or translation through any one of a number of antisense mechanisms. The sequence specificity of antisense compounds makes them attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in disease.

Duchenne muscular dystrophy (DMD) is caused by a defect in the expression of the protein dystrophin. The gene encoding the protein contains 79 exons spread out over more than 2 million nucleotides of DNA. Any exonic mutation that changes the reading frame of the exon, or introduces a stop codon, or is characterized by removal of an entire out of frame exon or exons, or duplications of one or more exons, has the potential to disrupt production of functional dystrophin, resulting in DMD.

Recent clinical trials testing the safety and efficacy of splice switching

oligonucleotides (SSOs) for the treatment of DMD are based on SSO technology to induce alternative splicing of pre-mRNAs by steric blockade of the spliceosome (Cirak et al., 2Q\ \; Goemans et al., 2011; Kinali et al., 2009; van Deutekom et al., 2007). However, despite these successes, the pharmacological options available for treating DMD are limited. Golodirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 53 of the human dystrophin gene in patients with DMD who are amendable to exon 53 skipping to restore the read frame and produce a functional shorter form of the dystrophin protein.

Although significant progress has been made in the field of antisense technology, there remains a need in the art for methods of preparing phosphorodiamidate morpholino oligomers with improved antisense or antigene performance.

PATENT

https://patents.google.com/patent/WO2017205880A1/en

Provided herein are processes for preparing phosphorodiamidate morpholino oligomers (PMOs). The synthetic processes described herein allow for a scaled-up PMO synthesis while maintaining overall yield and purity of a synthesized PMO.

Accordingly, in one aspect, provided herein is a process for preparing an oligomeric compound of Formula A):

Figure imgf000003_0001

(A).

In certain embodiments, provided herein is a process for preparing an oligomeric compound of Formula (G):

Figure imgf000004_0001

In yet another embodiment, the oligomeric compound of the disclosure including, for example, some embodiments of an oligomeric compound of Formula (G), is an oligomeric compound of Formula (XII):

Figure imgf000005_0001

(XII).

For clarity, the structural formulas including, for example, oligomeric compound of Formula (C) and Golodirsen depicted by Formula (XII), are a continuous structural formula from 5′ to 3′, and, for the convenience of depicting the entire formula in a compact form in the above structural formulas, Applicants have included various illustration breaks labeled “BREAK A” and “BREAK B.” As would be understood by the skilled artisan, for example, each indication of “BREAK A” shows a continuation of the illustration of the structural formula at these points. The skilled artisan understands that the same is true for each instance of “BREAK B” in the structural formulas above including Golodirsen. None of the illustration breaks, however, are intended to indicate, nor would the skilled artisan understand them to mean, an actual discontinuation of the structural formulas above including

Example 1: NCP2 Anchor Synthesis

1. Preparation of Meth l 4-Fluoro-3-Nitrobenzoate (1)

Figure imgf000103_0002

To a 100L flask was charged 12.7kg of 4-fluoro-3-nitrobenzoic acid was added 40kg of methanol and 2.82kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0° C. Crystals formed at 38° C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100L flask was washed and filter cake was washed with 10kg of methanol that had been cooled to 0° C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695kg methyl 4-fluoro-3-nitrobenzoate (100% yield; HPLC 99%).

2. Preparation of 3-Nitro-4-(2-oxopropyl)benzoic Acid

A. (Z)-Methyl 4-(3 -Hydroxy- l-Methoxy-l-Oxobut-2-en-2-yl)-3-Nitrobenzoate (2)

Figure imgf000104_0001

To a 100L flask was charged 3.98kg of methyl 4-fluoro-3-nitrobenzoate (1) from the previous step 9.8kg DMF, 2.81kg methyl acetoacetate. The mixture was stirred and cooled to 0° C. To this was added 3.66kg DBU over about 4 hours while the temperature was maintained at or below 5° C. The mixture was stirred an additional 1 hour. To the reaction flask was added a solution of 8.15kg of citric acid in 37.5kg of purified water while the reaction temperature was maintained at or below 15° C. After the addition, the reaction mixture was stirred an addition 30 minutes then filtered under nitrogen. The wet filter cake was returned to the 100L flask along with 14.8kg of purified water. The slurry was stirred for 10 minutes then filtered. The wet cake was again returned to the 100L flask, slurried with 14.8kg of purified water for 10 minutes, and filtered to crude (Z)-methyl 4-(3 -hydroxy- 1 – methoxy-l-oxobut-2-en-2-yl)-3-nitrobenzoate.

B. 3-Nitro-4-(2-oxopropyl)benzoic Acid

Figure imgf000105_0001

2 3

The crude (Z)-m ethyl 4-(3 -hydroxy- 1-methoxy-l -ox obut-2-en-2-yl)-3-nitrobenzoate was charged to a 100L reaction flask under nitrogen. To this was added 14.2kg 1,4-dioxane and the stirred. To the mixture was added a solution of 16.655kg concentrated HC1 and 13.33kg purified water (6M HC1) over 2 hours while the temperature of the reaction mixture was maintained below 15° C. When the addition was complete, the reaction mixture was heated at reflux (80° C) for 24 hours, cooled to room temperature, and filtered under nitrogen. The solid filter cake was triturated with 14.8kg of purified water, filtered, triturated again with 14.8kg of purified water, and filtered. The solid was returned to the 100L flask with 39.9kg of DCM and refluxed with stirring for 1 hour. 1.5kg of purified water was added to dissolve the remaining solids. The bottom organic layer was split to a pre-warmed 72L flask, then returned to a clean dry 100L flask. The solution was cooled to 0° C, held for 1 hour, then filtered. The solid filter cake was washed twice each with a solution of 9.8kg DCM and 5kg heptane, then dried on the funnel. The solid was transferred to trays and dried to a constant weight of 1.855kg 3-Nitro-4-(2-oxopropyl)benzoic Acid. Overall yield 42% from compound 1. HPLC 99.45%.

3. Preparation of N-Tritylpiperazine Succinate (NTP)

Figure imgf000105_0002

To a 72L jacketed flask was charged under nitrogen 1.805kg triphenylmethyl chloride and 8.3kg of toluene (TPC solution). The mixture was stirred until the solids dissolved. To a 100L jacketed reaction flask was added under nitrogen 5.61kg piperazine, 19.9kg toluene, and 3.72kg methanol. The mixture was stirred and cooled to 0° C. To this was slowly added in portions the TPC solution over 4 hours while the reaction temperature was maintained at or below 10° C. The mixture was stirred for 1.5 hours at 10° C, then allowed to warm to 14° C. 32.6kg of purified water was charged to the 72L flask, then transferred to the 100L flask while the internal batch temperature was maintained at 20+/-50 C. The layers were allowed to split and the bottom aqueous layer was separated and stored. The organic layer was extracted three times with 32kg of purified water each, and the aqueous layers were separated and combined with the stored aqueous solution.

The remaining organic layer was cooled to 18° C and a solution of 847g of succinic acid in 10.87kg of purified water was added slowly in portions to the organic layer. The mixture was stirred for 1.75 hours at 20+/-50 C. The mixture was filtered, and the solids were washed with 2kg TBME and 2kg of acetone then dried on the funnel. The filter cake was triturated twice with 5.7kg each of acetone and filtered and washed with 1kg of acetone between triturations. The solid was dried on the funnel, then transferred to trays and dried in a vacuum oven at room temperature to a constant weight of 2.32kg of NTP. Yield 80%. 4. Preparation of (4-(2-Hydroxypropyl)-3-NitrophenyI)(4-Tritylpiperazin-l-yl)Methanone A. Preparation of l-(2-Nitro-4(4-Tritylpiperazine-l-Carbonyl)Phenyl)Propan-2-one

Figure imgf000106_0001

3 4

To a 100L jacketed flask was charged under nitrogen 2kg of 3-Nitro-4-(2- oxopropyl)benzoic Acid (3), 18.3 kg DCM, 1.845kg N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (EDC.HC1). The solution was stirred until a homogenous mixture was formed. 3.048kg of NTP was added over 30 minutes at room temperature and stirred for 8 hours. 5.44kg of purified water was added to the reaction mixture and stirred for 30 minutes. The layers were allowed to separate and the bottom organic layer containing the product was drained and stored. The aqueous layer was extracted twice with 5.65kg of DCM. The combined organic layers were washed with a solution of 1.08kg sodium chloride in 4.08kg purified water. The organic layers were dried over 1.068kg of sodium sulfate and filtered. The sodium sulfate was washed with 1.3kg of DCM. The combined organic layers were slurried with 252g of silica gel and filtered through a filter funnel containing a bed of 252g of silica gel. The silica gel bed was washed with 2kg of DCM. The combined organic layers were evaporated on a rotovap. 4.8kg of THF was added to the residue and then evaporated on the rotovap until 2.5 volumes of the crude l-(2-nitro-4(4-tritylpiperazine-l- carbonyl)phenyl)propan-2-one in THF was reached.

B. Preparation of (4-(2-Hydroxypropyl)-3-NitrophenyI)(4-Tritylpiperazin-l- yl)Methano

Figure imgf000107_0001

To a 100L jacketed flask was charged under nitrogen 3600g of 4 from the previous step and 9800g THF. The stirred solution was cooled to <5° C. The solution was diluted with 11525g ethanol and 194g of sodium borohydride was added over about 2 hours at <5° C. The reaction mixture was stirred an additional 2 hours at <5° C. The reaction was quenched with a solution of about 1.1kg ammonium chloride in about 3kg of water by slow addition to maintain the temperature at <10° C. The reaction mixture was stirred an additional 30 minutes, filtered to remove inorganics, and recharged to a 100L jacketed flask and extracted with 23kg of DCM. The organic layer was separated and the aqueous was twice more extracted with 4.7kg of DCM each. The combined organic layers were washed with a solution of about 800g of sodium chloride in about 3kg of water, then dried over 2.7kg of sodium sulfate. The suspension was filtered and the filter cake was washed with 2kg of DCM. The combined filtrates were concentrated to 2.0 volumes, diluted with about 360g of ethyl acetate, and evaporated. The crude product was loaded onto a silica gel column of 4kg of silica packed with DCM under nitrogen and eluted with 2.3kg ethyl acetate in 7.2kg of DCM. The combined fractions were evaporated and the residue was taken up in 11.7kg of toluene. The toluene solution was filtered and the filter cake was washed twice with 2kg of toluene each. The filter cake was dried to a constant weight of 2.275kg of compound 5 (46% yield from compound 3) HPLC 96.99%. 5. Preparation of 2,5-Dioxopyrrolidin-l-yl(l-(2-Nitro-4-(4-triphenylmethylpiperazine-l Carbon l)Phenyl)Propan-2-yl) Carbonate (NCP2 Anchor)

Figure imgf000108_0001

3 NCP2 Anchor

To a 100L jacketed flask was charged under nitrogen 4.3kg of compound 5 (weight adjusted based on residual toluene by 1H MR; all reagents here after were scaled accordingly) and 12.7kg pyridine. To this was charged 3.160 kg of DSC (78.91 weight % by 1H NMR) while the internal temperature was maintained at <35° C. The reaction mixture was aged for about 22 hours at ambience then filtered. The filter cake was washed with 200g of pyridine. In two batches each comprising ½ the filtrate volume, filtrate wash charged slowly to a 100L jacketed flask containing a solution of about 11kg of citric acid in about 50 kg of water and stirred for 30 minutes to allow for solid precipitation. The solid was collected with a filter funnel, washed twice with 4.3kg of water per wash, and dried on the filter funnel under vacuum.

The combined solids were charged to a 100L jacketed flask and dissolved in 28kg of DCM and washed with a solution of 900g of potassium carbonate in 4.3kg of water. After 1 hour, the layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with 10kg of water, separated, and dried over 3.5kg of sodium sulfate. The DCM was filtered, evaporated, and dried under vacuum to 6.16kg of NCP2 Anchor (114% yield).

Example 2: Anchor Loaded Resin Synthesis

To a 75L solid phase synthesis reactor was charged about 52L of NMP and 2600g of aminomethyl polystyrene resin. The resin was stirred in the NMP to swell for about 2 hours then drained. The resin was washed twice with about 39L DCM per wash, then twice with 39L Neutralization Solution per wash, then twice with 39L of DCM per wash. The NCP2 Anchor Solution was slowly added to the stirring resin solution, stirred for 24 hours at room temperature, and drained. The resin was washed four times with 39L of NMP per wash, and six times with 39L of DCM per wash. The resin was treated and stirred with ½ the DEDC Capping Solution for 30 minutes, drained, and was treated and stirred with the 2nd ½ of the DEDC Capping Solution for 30 minutes and drained. The resin was washed six times with 39L of DCM per wash then dried in an oven to constant weight of 3573.71g of Anchor Loaded Resin.

Example 3: Preparation of Activated EG3 Tail

1. Preparation of Trityl Piperazine Phenyl Carbamate 35

Figure imgf000109_0001

To a cooled suspension of NTP in dichloromethane (6 mL/g NTP) was added a solution of potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate). To this two- phase mixture was slowly added a solution of phenyl chloroformate (1.03 eq) in

dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20° C. Upon reaction completion (1-2 hr), the layers were separated. The organic layer was washed with water, and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. Yield=80%

2. Preparation of Carbamate Alcohol (36)

Figure imgf000110_0001

Sodium hydride (1.2 eq) was suspended in l-methyl-2-pyrrolidinone (32 mL/g sodium hydride). To this suspension were added triethylene glycol (10.0 eq) and compound 35 (1.0 eq). The resulting slurry was heated to 95° C. Upon reaction completion (1-2 hr), the mixture was cooled to 20° C. To this mixture was added 30% dichloromethane/methyl tert- butyl ether (v:v) and water. The product-containing organic layer was washed successively with aqueous NaOH, aqueous succinic acid, and saturated aqueous sodium chloride. The product 36 was isolated by crystallization from dichloromethane/methyl tert-butyl ether/heptane. Yield=90%.

3. Preparation of EG3 Tail Acid (37)

Figure imgf000110_0002

To a solution of compound 36 in tetrahydrofuran (7 mL/g 36) was added succinic anhydride (2.0 eq) and DMAP (0.5 eq). The mixture was heated to 50° C. Upon reaction completion (5 hr), the mixture was cooled to 20° C and adjusted to pH 8.5 with aqueous NaHC03. Methyl tert-butyl ether was added, and the product was extracted into the aqueous layer. Dichloromethane was added, and the mixture was adjusted to pH 3 with aqueous citric acid. The product-containing organic layer was washed with a mixture of pH=3 citrate buffer and saturated aqueous sodium chloride. This dichloromethane solution of 37 was used without isolation in the preparation of compound 38. 4. Preparation of Activated EG3 Tail (38)

Figure imgf000111_0001

To the solution of compound 37 was added N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) (1.02 eq), 4-dimethylaminopyridine (DMAP) (0.34 eq), and then l-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) (1.1 eq). The mixture was heated to 55° C. Upon reaction completion (4-5 hr), the mixture was cooled to 20° C and washed successively with 1 : 1 0.2 M citric acid/brine and brine. The dichloromethane solution underwent solvent exchange to acetone and then to Ν,Ν-dimethylformamide, and the product was isolated by precipitation from acetone/N,N-dimethylformamide into saturated aqueous sodium chloride. The crude product was reslurried several times in water to remove residual Ν,Ν-dimethylformamide and salts. Yield=70% of Activated EG3 Tail 38 from compound 36.

Example 4: 50L Solid-phase Synthesis of

Golodirsen [Oligomeric Compound (XII)] Crude Drug Substance

1. Materials

Table 2: Starting Materials

Figure imgf000111_0002

Activated Phosphoramidochloridic acid, 1155373-31-1 C37H37CIN5O5P 698.2 C Subunit N,N-dimethyl-,[6-[4-

(benzoylamino)-2-oxo-l(2H)- pyrimidinyl]-4-

(triphenylmethyl)-2- morpholinyljmethyl ester

Activated Propanoic Acid, 2,2-dimethyl- 1155309-89-9 C5iH53ClN707P 942.2

DPG ,4-[[[9-[6-

Subunit [[[chloro(dimethylamino)phosp

hinyl]oxy]methyl]-4-

(triphenylmethyl)-2- morpholinyl]-2-[(2- phenylacetyl)amino]-9H-purin-

6-yl]oxy]methyl]phenyl ester

Activated Phosphoramidochloridic acid, 1155373-34-4 C3iH34ClN405P 609.1 T Subunit N,N-dimethyl-,[6-(3,4-dihydro- 5-methyl-2,4-dioxo- 1 (2H)- pyrimidinyl)]-4- (triphenylmethyl)-2- morpholinyljmethyl ester

Activated Butanedioic acid, 1- 1380600-06-5 C43H47N3Oio 765.9 EG3 Tail [3aR,4S,7R,7aS)-l,3,3a,4,7,7a- hexahydro- 1 ,3 -dioxo-4,7- methano-2H-isoindol-2-yl] 4- [2-[2-[2-[[[4-(triphenylmethyl)- 1- piperazinyl ] carb onyl ] oxy] ethox

y]ethoxy] ethyl] ester

Golodirsen.

Example 5: Purification of Golodirsen Crude Drug Substance

The deprotection solution from Example 4, part E, containing the Golodirsen crude drug substance was loaded onto a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience) and eluted with a gradient of 0-35% B over 17 column volume (Buffer A: 10 mM sodium hydroxide; Buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and fractions of acceptable purity (CI 8 and SCX HPLC) were pooled to a purified drug product solution. HPLC: 93.571% (C18; Fig. 3) 88.270% (SCX; Fig. 4).

The purified drug substance solution was desalted and lyophilized to 1450.72 g purified Golodirsen drug substance. Yield 54.56 %; HPLC: 93.531% (Fig. 5; C18) 88.354% (Fig. 6; SCX).

PATENT

WO 2019067979

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019067979&tab=PCTDESCRIPTION&_cid=P22-K4DLNX-74378-1

Duchenne Muscular Dystrophy (DMD) is a serious, progressively debilitating, and ultimately fatal inherited X-linked neuromuscular disease. DMD is caused by mutations in the dystrophin gene characterized by the absence, or near absence, of functional dystrophin protein that disrupt the mRNA reading frame, resulting in a lack of dystrophin, a critically important part of the protein complex that connects the cytoskeletal actin of a muscle fiber to the extracellular matrix. In the absence of dystrophin, patients with DMD follow a predictable disease course. Affected patients, typically boys, develop muscle weakness in the first few years of life, lose the ability to walk during childhood, and usually require respiratory support by their late teens. Loss of functional abilities leads to loss of independence and increasing caregiver burden. Once lost, these abilities cannot be recovered. Despite improvements in the standard of care, such as the use of glucocorticoids, DMD remains an ultimately fatal disease, with patients usually dying of respiratory or cardiac failure in their mid to late 20s.

Progressive loss of muscle tissue and function in DMD is caused by the absence or near absence of functional dystrophin; a protein that plays a vital role in the structure and function of muscle cells. A potential therapeutic approach to the treatment of DMD is suggested by Becker muscular dystrophy (BMD), a milder dystrophinopathy. Both dystrophinopathies are caused by mutations in the DMD gene. In DMD, mutations that disrupt the pre-mRNA reading frame,

referred to as “out-of-frame” mutations, prevent the production of functional dystrophin. In BMD, “in-frame” mutations do not disrupt the reading frame and result in the production of internally shortened, functional dystrophin protein.

An important approach for restoring these “out-of-frame” mutations is to utilize an antisense oligonucleotide to exclude or skip the molecular mutation of the DMD gene

(dystrophin gene). The DMD or dystrophin gene is one of the largest genes in the human body and consists of 79 exons. Antisense oligonucleotides (AONs) have been specifically designed to target specific regions of the pre-mRNA, typically exons to induce the skipping of a mutation of the DMD gene thereby restoring these out-of-frame mutations in-frame to enable the production of internally shortened, yet functional dystrophin protein.

The skipping of exon 53 in the dystrophin gene has been an area of interest for certain research groups due to it being the most prevalent set of mutations in this disease area, representing 8% of all DMD mutations. A prominent AON being developed by Sarepta

Therapeutics, Inc., for DMD patients that are amenable to exon 53 skipping is golodirsen.

Golodirsen is a phosphorodiamidate morpholino oligomer, or PMO. Another AON being developed by Nippon Shinyaku CO., LTD., for DMD patients that are amenable to exon 53 skipping is viltolarsen (NS-065 which is a PMO.

Exondys 51 ® (eteplirsen), is another PMO that was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. However, the current standard of care guidelines for the treatment of DMD in patients that are not amenable to exon 51 skipping include the administration of glucocorticoids in conjunction with palliative interventions. While glucocorticoids may delay the loss of ambulation, they do not sufficiently ameliorate symptoms, modify the underlying genetic defect or address the absence of functional dystrophin characteristic of DMD.

Previous studies have tested the efficacy of an antisense oligonucleotides (AON) for exon skipping to generate at least partially functional dystrophin in combination with a steroid for reducing inflammation in a DMD patient (see WO 2009/054725 and van Deutekom, et al., N. Engl. J. Med. 2007; 357:2677-86, the contents of which are hereby incorporated herein by reference for all purposes). However, treatment with steroids can result in serious complications, including compromise of the immune system, reduction in bone strength, and growth

suppression. Notably, none of the previous studies suggest administering an antisense

oligonucleotide for exon skipping with a non-steroidal anti-inflammatory compound to a patient for the treatment of DMD.

Thus, there remains a need for improved methods for treating muscular dystrophy, such as DMD and BMD in patients.

EXAMPLE 1

CAT- 1004 in Combination with M23D PMO Reduces Inflammation and Fibrosis in Mdx Mice.

To assess the effectiveness of a combination treatment of an exon skipping antisense oligonucleotide and an F-Kb inhibitor in Duchenne muscular dystrophy, M23D PMO and

CAT-1004 were utilized in the Mdx mouse model. The effect on inflammation and fibrosis was determined by analyzing samples of muscle taken from the quadriceps, of (1) wild-type mice treated with saline, (2) mdx mice treated with saline, (3) mdx mice treated with CAT-1004, (4) mdx mice treated with the M23D PMO, and (5) mdx mice treated with the M23D PMO in combination with CAT-1004. The tissue sections were analyzed for fibrosis by picrosirius red staining and for inflammation and fibrosis by Hematoxylin and Eosin (H&E) staining, as described in the Materials and Methods section above.

Treatment of Mdx mice with either M23D PMO or CAT-1004 as monotherapies resulted in a reduction of inflammation and fibrosis as compared to Mdx mice treated with saline.

Surprisingly, treatment of Mdx mice with the M23D PMO in combination with CAT-1004 resulted in reduced inflammation and fibrosis as compared with mice treated with CAT-1004

alone or M23D alone (Fig. 9). These results indicate the combination treatment enhances muscle fiber integrity.

EXAMPLE 2

Exon Skipping and Dystrophin Production in Mdx Mice Treated with the M23D

PMO and the M23D PMO in Combination with CAT- 1004

To analyze the extent of exon skipping and dystrophin production in mice treated with the M23D PMO in combination with CAT- 1004, samples of muscle were taken from the quadriceps, diaphragm, and heart of (1) wild-type mice treated with saline, (2) mdx mice treated with saline, (3) mdx mice treated with CAT- 1004, (4) mdx mice treated with the M23D PMO, and (5) mdx mice treated with the M23D PMO in combination with CAT- 1004. RT-PCR analysis for exon 23 skipping was performed as well as Western blot analysis to determine dystrophin protein levels.

Exon skipping was observed in the muscle of the quadriceps, diaphragm, and heart of the Mdx mice treated with the M23D PMO as well as mice treated with the M23D PMO in combination with CAT-1004 (Fig. 10). Surprisingly, enhanced dystrophin production was observed in the muscle of the quadriceps, diaphragm, and heart of the mice treated with the M23D PMO in combination with CAT-1004 as compared to treatment with M23D PMO monotherapy (Fig. 11). These results indicated the increase in dystrophin levels extended to the heart, a tissue known to have low efficiency of dystrophin upregulation by these agents when used alone. Notably, neither exon skipping nor dystrophin production were observed in mdx mice treated with CAT-1004 monotherapy (Figs. 10 and 11).

PATENT

WO 2019046755

PAPER

Methods in Molecular Biology (New York, NY, United States) (2018), 1828(Exon Skipping and Inclusion Therapies), 31-55.

PAPER

Human Molecular Genetics (2018), 27(R2), R163-R172.

///////////Golodirsen, ゴロジルセン , FDA 2019, ANTISENSE, Exon 53: NG-12-0163, SRP 4053, OLIGONUCLEOTIDE, Duchenne Muscular Dystrophy

FDA approves new treatment XCOPRI (cenobamate tablets) for adults with partial-onset seizures


The U.S. Food and Drug Administration today approved XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults.
“XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”
A seizure is a usually short episode of abnormal electrical activity in the brain. Seizures can cause uncontrolled movements,  abnormal thinking or behavior, and abnormal sensations. Movements can be violent, and changes in consciousness can occur. Seizures occur when clusters of nerve cells (neurons) in the brain undergo uncontrolled activation. A partial-onset seizure begins in a limited area of the brain.
The safety and efficacy of XCOPRI to treat partial-onset seizures was established in two randomized, double-blind, placebo-controlled studies that enrolled 655 adults. In these studies, patients had partial-onset seizures with or without secondary generalization for an average of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days during an 8-week baseline period. During the trials, doses of 100, 200, and 400 milligrams (mg) daily of XCOPRI reduced the percent of seizures per 28 days compared with the placebo group. The recommended maintenance dose of XCOPRI, following a titration (medication adjustment) period, is 200 mg daily; however, some patients may need an additional titration to 400 mg daily, the maximum recommended dose, based on their clinical response and tolerability.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported among patients taking XCOPRI. In the clinical trials, some patients experienced DRESS, and one patient died, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1,339 epilepsy patients when XCOPRI was started at 12.5 mg per day and adjusted every two weeks; however, this finding does not show that the risk of DRESS is prevented by a slower titration. A higher percentage of patients who took XCOPRI also had a shortening of the QT interval (an assessment of certain electrical properties of the heart) of greater than twenty milliseconds compared to placebo. XCOPRI should not be used in patients with hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI or Familial Short QT syndrome. QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.
Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients taking an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. XCOPRI may cause neurological adverse reactions, including somnolence (sleepiness) and fatigue, dizziness, trouble with walking and coordination, trouble with thinking, and visual changes. Patients should also be advised not to drive or operate machinery until the effect of XCOPRI is known.
The most common side effects that patients in the clinical trials reported were somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), and headaches.
The FDA granted the approval of XCOPRI to SK Life Science Inc.
////////fda 2019, XCOPRI, cenobamate, SK Life Science

FDA approves first treatment Givlaari (givosiran) for inherited rare disease


Today, the U.S. Food and Drug Administration granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”
The approval of Givlaari was based on the results of a clinical trial of 94 patients with acute hepatic porphyria. Patients received a placebo or Givlaari. Givlaari’s performance was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Patients who received Givlaari experienced 70% fewer porphyria attacks compared to patients receiving a placebo.
Common side effects for patients taking Givlaari were nausea and injection site reactions. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function. Patients should have their liver function tested before and periodically during treatment.
The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Givlaari also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals.

http://s2027422842.t.en25.com/e/es?s=2027422842&e=277662&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=d02d631b3809408d94ccf3f5bec31dbd&elqaid=10358&elqat=1

///////////Givlaari, givosiran, fda 2019, Breakthrough Therapy designation,  Priority ReviewOrphan Drug

Afamelanotide, アファメラノチド , афамеланотид , أفاميلانوتيد , 阿法诺肽 ,


Melanotan.png

2D chemical structure of 75921-69-6

ChemSpider 2D Image | Afamelanotide | C78H111N21O19

Click here for structure editor

Afamelanotide

RN: 75921-69-6

Molecular Formula, C78-H111-N21-O19, Molecular Weight, 1646.8629

Synonyms

  • 75921-69-6
  • AFAMELANOTIDE [MI]
  • AFAMELANOTIDE
  • AFAMELANOTIDE [INN]
  • .ALPHA.-MELANOTROPIN (SWINE), 4-L-NORLEUCINE-7-D-PHENYLALANINE-
  • AC-SER-TYR-SER-NLE-GLU-HIS-D-PHE-ARG-TRP-GLY-LYS-PRO-VAL-NH2
  • CUV1647
  • AFAMELANOTIDE [WHO-DD]
  • AFAMELANOTIDE [USAN]
  • ACETYL(4-(2S)-2-AMINOHEXANOIC ACID,7-D-PHENYLALANINE)HUMAN MELANOTROPIN ALPHA
  • CUV-1647
  • MELANOTAN I
  • MELANOTAN-1

alpha-Melanotropin, 4-L-norleucine-7-D-phenylalanine-

Prevention of Phototoxicity in Adults with Erythropoietic Protoporphyria (EPP)

UNII: QW68W3J66U

アファメラノチド;

афамеланотид [Russian] [INN]
أفاميلانوتيد [Arabic] [INN]
阿法诺肽 [Chinese] [INN]

Observations suggest that afamelanotide has beneficial effects in patients with erythropoietic protoporphyria, induces epidermal melanin formation.

SYN

Lensing, Cody J. et alFrom Journal of Medicinal Chemistry, 62(1), 144-158; 2019

FDA APPROVED

oct 2019

FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder

http://s2027422842.t.en25.com/e/es?s=2027422842&e=262817&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=e8d49092f54446349d8b5eb52a13e7a1&elqaid=9807&elqat=1

The U.S. Food and Drug Administration today granted approval to Scenesse (afamelanotide) to increase pain-free light exposure in adult patients with a history of phototoxic reactions (damage to skin) from erythropoietic protoporphyria.

For patients who are suffering from erythropoietic protoporphyria, a rare disorder, exposure to light may be extremely painful. Prior to today’s approval, there were no FDA-approved treatments to help erythropoietic protoporphyria patients increase their light exposure,” said Julie Beitz, M.D., director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III. “Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible.”

Erythropoietic protoporphyria is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production. Heme is an important component in hemoglobin, the oxygen carrying molecule in red blood cells. The decrease in ferrochelatase activity leads to an accumulation of protoporphyrin IX (PPIX) in the body. Light reaching the skin can react with PPIX causing intense skin pain and skin changes, such as redness and thickening. Scenesse (afamelanotide), a melanocortin-1 receptor (MC1-R) agonist, increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources.  It is an implant that is administered subcutaneously (inserted under the skin).

The efficacy of Scenesse was established in two parallel group clinical trials with patients with erythropoietic protoporphyria who received Scenesse or placebo form of the implant subcutaneously every two months. The first clinical trial enrolled 93 subjects, of whom 48 received Scenesse, and were followed for 180 days. The primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain. The median total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain was 64 hours for patients receiving Scenesse and 41 hours for patients taking placebo.

The second clinical trial enrolled 74 patients, of whom 38 received Scenesse, and were followed for 270 days. The primary endpoint was the total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight. The analysis did not include sun exposure on days patients reported spending time in a combination of both direct sunlight and shade. The median total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight was six hours for patients receiving Scenesse and 0.75 hours for patients receiving placebo.

Scenesse’s most common side effects are implant site reaction, nausea, oropharyngeal (part of the throat just behind the mouth, where the oral cavity starts) pain, cough, fatigue, skin hyperpigmentation, dizziness, melanocytic nevus (moles), respiratory tract infection, somnolence (feeling drowsy), non-acute porphyria (build-up of normally occurring molecules created during heme production) and skin irritation. Scenesse should be administered by a health care professional who is proficient in the subcutaneous implantation procedure and has completed the applicant-provided training. Scenesse may induce skin darkening, and a full body skin examination is recommended for patients twice a year. In addition, patients are encouraged to maintain sun protection measures during treatment with Scenesse to prevent phototoxic reactions related to erythropoietic protoporphyria.

The FDA granted this application Priority Review designation. Scenesse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.The approval of Scenesse was granted to Clinuvel.

For more information:

Afamelanotide (melanotan ICUV1647; brand name Scenesse)[2] is a synthetic peptide and analogue of α-melanocyte stimulating hormone used to prevent skin damage from the sun in people with erythropoietic protoporphyria in Europe since January 2015. It is administered as an implant that is placed under the skin; the implant lasts for two months.

It is under development in other skin disorders in several jurisdictions. It causes skin to turn darker by causing the skin to make more melanin.

It was discovered at University of Arizona and initially developed there as a sunless tanning agent; the Australian company Clinuvel conducted further clinical trials in that and other indications, and brought the drug to market.

Unlicensed and untested powders sold as “melanotan” are found on the Internet marketed for tanning and other purposes, and multiple regulatory bodies have warned consumers that the peptides may be unsafe and ineffective.

Medical use

Afamelanotide is used in Europe to prevent phototoxicity in adults with erythropoietic protoporphyria (EPP).[1] It is an implant that is injected and placed under the skin; an implant lasts two months.[1]

People who have severe liver disease, liver impairment, or kidney impairment, should not use this drug. Pregnant women should not take it, and women who are active sexually should use contraception while they are taking it. It is not known if afamelanotide is secreted in breast milk.[1]

Adverse effects

Very common (up to 10% of people) adverse effects in people with EPP include headache and nausea. Common (between 1% and 10%) adverse effects include back pain, upper respiratory tract infections, decreased appetite, migraine, dizziness, weakness, fatigue, lethargy, sleepiness, feeling hot, stomach pain, diarrhea, vomiting, flushing and red skin, development of warts, spots, and freckles, itchy skin, and reactions at the injection site. There are many uncommon (less than 1%) adverse effects.[1]

Pharmacology

Afamelanotide is thought to cause skin to darken by binding to the melanocortin 1 receptor which in turn drives melanogenesis.[1]

Afamelanotide has a half-life of 30 minutes. After the implant is injected, most of the drug is released within the first 2 days, with 90% released by the fifth day. By the tenth day no drug is detectable in plasma.[1]

Its metabolites, distribution, metabolism and excretion were not understood as of 2017.[1]

Chemistry

The amino acid sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, and it is additionally known as [Nle4,D-Phe7]-α-MSH, which is sometimes abbreviated as NDP-MSH or NDP-α-MSH. Afamelanotide is the International Nonproprietary Name.[3]

History

The role of α-MSH in promoting melanin diffusion has been known since the 1960s.[4] In the 1980s, scientists at University of Arizona began attempting to develop α-MSH and analogs as potential sunless tanning agents, and synthesized and tested several analogs, including melanotan-I.[5]

To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan,[6][5] which changed its name to Clinuvel in 2006.[7]

Early clinical trials showed that the peptide had to be injected about ten times a day due to its short half-life, so the company collaborated with Southern Research in the US to develop a depot formulation that would be injected under the skin, and release the peptide slowly. This was done by 2004.[6]

As of 2010, afamelanotide was in Phase III trials for erythropoietic protoporphyria and polymorphous light eruption, and was in Phase II trials for actinic keratosis and squamous cell carcinoma, and had been trialled in phototoxicity associated with systemic photodynamic therapy and solar urticaria.[8] Clinuvel had also obtained orphan drug status for afamelanotide in the US and the EU by that time.[8]

In May 2010 the Italian Medicines Agency (AIFA, or Agenzia Italiana del Farmaco) approved afamelanotide as a treatment for erythropoietic protoporphyria.[9]

In January 2015 afamelanotide was approved by the EMA in Europe for the treatment of phototoxicity in people with EPP.[1]

Society and culture

Counterfeits

A number of products are sold online and in gyms and beauty salons as “melanotan” or “melanotan-1” which discuss afamelanotide in their marketing.[10][11] [12]

The products are not legal in any jurisdiction and are dangerous.[13][14][15][16]

Starting in 2007 health agencies in various counties began issuing warnings against their use.[17][18][19][20] [21][22]

PAPERS

Sawyer T K; Sanfilippo P J; Hruby V J; Engel M H; Heward C B; Burnett J B; Hadley M E

  • From Proceedings of the National Academy of Sciences of the United States of America (1980), 77(10), 5754-8.

2 Journal of Medicinal Chemistry (1982), 25(9), 1022-7.

3 Journal of medicinal chemistry (1984), 27(11), 1406-10.

4 Journal of Medicinal Chemistry (2019), 62(1), 144-158

5 Journal of Medicinal Chemistry (2018), 61(17), 7729-7740.

6 Journal of medicinal chemistry (2017), 60(2), 805-813.

PATENT

US 4457864

References

  1. Jump up to:a b c d e f g h i “Scenesse: Summary of Product Characteristics” (PDF). EMA. 27 January 2016. Retrieved 6 April 2017. For updates see EMA Index page
  2. ^ “Afamelanotide”. AdisInsight. Retrieved 6 April 2017.
  3. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)World Health Organization. 2009. Retrieved 2009-03-02.
  4. ^ Baker, BI (31 May 1993). “The role of melanin-concentrating hormone in color change”. Annals of the New York Academy of Sciences680: 279–89. doi:10.1111/j.1749-6632.1993.tb19690.xPMID 8390154.
  5. Jump up to:a b Hadley, ME; Dorr, RT (April 2006). “Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization”. Peptides27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029PMID 16412534.
  6. Jump up to:a b “EpiTan focuses on Melanotan, a potential blockbuster”The Pharma Letter. 1 November 2004.
  7. ^ “Epitan changes name to Clinuvel, announces new clinical program”LabOnline. 27 February 2006.
  8. Jump up to:a b Dean, Tim (3 May 2010). “Biotechnology profile: Bright future for Clinuvel (ASX:CUV)”Australian Life Scientist. Archived from the original on 6 April 2017.
  9. ^ “GAZZETTA UFFICIALE: SOMMARIO”Agenzia Nazionale Stampa Associata. 2010. Retrieved 2010-05-17.
  10. ^ “Believe It Or Not ‘Tanorexia’ A Very Real Problem”WCBS-TVCBS. 2009-05-20. Archived from the original on May 21, 2009. Retrieved 2009-07-23.
  11. ^ “Fools Gold”Cosmopolitan (Australia). 2009-06-14. Retrieved 2009-07-25.
  12. ^ Madrigal, Alexis (2009-01-29). “Suntan Drug Greenlighted for Trials”WiredArchivedfrom the original on 5 May 2009. Retrieved 2009-04-11.
  13. ^ “Tanning drug a health risk”Herald Sun. 2009-10-31. Retrieved 2009-10-31.
  14. ^ Ewan A Langan; Z. Nie; Lesley E Rhodes (June 2010). “Melanotropic peptides: More than just “Barbie drugs” and “sun tan jabs?“. British Journal of Dermatology163 (3): 451–5. doi:10.1111/j.1365-2133.2010.09891.xPMID 20545686.
  15. ^ Ewan A Langan; Denise Ramlogan; Lynne A Jamieson; Lesley E Rhodes (January 2009). “Change in moles linked to use of unlicensed “sun tan jab“. BMJ338: b277. doi:10.1136/bmj.b277PMID 19174439.
  16. ^ “Risky tan jab warnings ‘ignoredBBC. 2009-02-18. Archived from the original on 21 February 2009. Retrieved 2009-03-04.
  17. ^ “Warning against the product Melanotan”Danish Medicines Agency. 2008. Retrieved 2008-08-11.
  18. ^ Tan jab” is an unlicensed medicine and may not be safe”MHRA. 2008. Archived from the original on 2014-12-05. Retrieved 2008-11-17.
  19. ^ “US Lab Research Inc Warning letter”. U.S. Food and Drug Administration. 2009-01-29. Archived from the original on 10 July 2009. Retrieved 2009-07-23.
  20. ^ “Melanotan Powder for Injection”Notice Information: – Warning – 27 February 2009Irish Medicines Board. 2009. Retrieved 2009-02-02.
  21. ^ “Legemiddelverket advarer mot bruk av Melanotan”. Norwegian Medicines Agency. 2007-12-13. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
  22. ^ “Melanotan – farlig og ulovlig brunfarge”Norwegian Medicines Agency. 2009-01-23. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
Afamelanotide
Melanotan.png
Clinical data
Pronunciation /ˌæfəmɛˈlæntd/ (About this soundlisten)
Trade names Scenesse
Synonyms Melanotan; Melanotan-1; Melanotan I; CUV1647; EPT1647; NDP-MSH; NDP-α-MSH; [Nle4,D-Phe7]α-MSH
AHFS/Drugs.com UK Drug Information
License data
Routes of
administration
S.C.I.M.I.V.subcutaneous implantintranasal
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Elimination half-life 30 minutes[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C78H111N21O19
Molar mass 1646.845 g/mol g·mol−1
3D model (JSmol)

/////////////fda 2019, Scenesse, afamelanotide,  pain-free light exposure,  erythropoietic protoporphyria, アファメラノチド , афамеланотид أفاميلانوتيد 阿法诺肽 

Afamelanotide acetate [USAN]
1566590-77-9

MW: 1706.9145

2D chemical structure of 1566590-77-9

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