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PRITELIVIR MESYLATE
PRITELIVIR MESYLATE
CAS 1428333-96-3
1428321-10-1 HYDRATE
FREE FORM
AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate
BAY57-1293; BAY 57-1293; BAY-57-1293; BAY571293; BAY 571293; BAY-571293; AIC-316; AIC 316
| Molecular Weight | 516.61 |
|---|---|
| Synonyms | AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate |
| Formula | C19H24N4O7S3 |
| CAS No. | 1428321-10-1 |
Pritelivir mesylate is an antiviral drug currently under development, specifically targeting herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). It functions by inhibiting the viral helicase-primase enzyme, a crucial component for HSV replication. It is being investigated as a potential treatment for various herpes infections, including those resistant to traditional antivirals like acyclovir.
Key aspects of Pritelivir mesylate:
- Mechanism of Action:Pritelivir is a helicase-primase inhibitor, meaning it blocks the activity of an enzyme essential for the replication of herpes viruses.
- Target Viruses:It is effective against both HSV-1 and HSV-2, the viruses responsible for cold sores and genital herpes, respectively.
- Potential for Resistance:Pritelivir has shown promise in preclinical studies against acyclovir-resistant strains of HSV, making it a potential alternative for patients with drug-resistant infections.
- Clinical Trials:Pritelivir is currently in phase II clinical trials, with ongoing research into its effectiveness and safety.
- Route of Administration:It is being investigated for oral, topical, and vaginal administration.
- Research and Development:Pritelivir is being developed by AiCuris Anti-infective Cures, building upon research from Bayer.
Pritelivir (development codes AIC316 or BAY 57-1293) is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.
SCHEME
Pritelivir mesylate, an antiviral drug used to treat herpes simplex virus (HSV) infections, is synthesized through a series of chemical reactions, including palladium-catalyzed coupling, ester saponification, and amide coupling reactions. The mesylate salt is then formed by reacting the free base with methanesulfonic acid.
Detailed Synthesis Steps:
- 1. Diaryl Acetic Acid Synthesis:Diaryl acetic acid reagents are synthesized using palladium-catalyzed coupling reactions. These reactions involve the use of organometallic intermediates derived from halo-aryl esters.
- 2. Ester Saponification:The ester group in the synthesized compounds is then converted to a carboxylic acid group through saponification.
- 3. Amide Coupling:The resulting carboxylic acids are coupled with thiazolyl sulfonamides using amide coupling conditions to form the pritelivir molecule.
- 4. Salt Formation:The pritelivir free base is then reacted with methanesulfonic acid to form the mesylate salt, which is the active pharmaceutical ingredient (API).
Key Aspects of Pritelivir Mesylate Synthesis:
- Targeted Mechanism:Pritelivir mesylate inhibits the herpes simplex virus by targeting the viral helicase-primase complex, essential for DNA replication, unlike traditional antivirals that target DNA polymerase.
- Salt and Polymorph Screening:An extensive salt and polymorph screening is performed to optimize the pharmaceutical development of pritelivir, resulting in various salt forms including the mesylate, maleate, and sulfate.
- Solubility and Stability:Pritelivir mesylate is a BCS Class II drug substance with pH-dependent solubility. It exhibits high solubility below pH 3 and poor solubility at neutral pH.
- Formulation Considerations:Due to its limited water solubility, pritelivir mesylate is often formulated with solvents like DMSO, PEG300, Tween-80, and saline or with cyclodextrins like SBE-β-CD.
- Clinical Trials:Pritelivir mesylate is currently under extensive study to evaluate its efficacy and safety profile, with promising results in early clinical trials.
PATENT
WO2018096170
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018096170&_cid=P20-MCVCP5-34284-1
PATENT
WO2018096177
PATENT
https://patents.google.com/patent/WO2018096177A1/en
Likewise, EP 2 598 502 Al describes the crystalline mono mesylate monohydrate salt of N- [5-(aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetar^ in a definite particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said N-[5- (aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide mono mesylate monohydrate having the afore-mentioned particle size distribution and specific surface area range.
WO 2013/045479 Al describes an improved and shortened synthesis process of N-[5- (ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide and the mesylate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds. Moreover, also the crystalline mesylate monohydrate salt of N- [5 -(aminosulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)-phenyl] – acetamide is described therein with increased long-term stability and release kinetics from pharmaceutical compositions thereof.
Said pritelivir is an innovative, highly active and specific inhibitor of herpes simplex virus (HSV) infections. As a compound derived from the chemical class of thiazolylamides, pritelivir is active against both types of herpes simplex virus causing labial and genital herpes, respectively, and retains activity against viruses which have become resistant to marketed drugs. Pritelivir has a mode of action that is distinct from other antiviral agents currently in use for treatment of HSV infections (i.e., the nucleoside analogues acyclovir and its prodrug valacyclovir as well as famciclovir, the prodrug of penciclovix). Whereas nucleoside analogs terminate ongoing DNA chain elongation through inhibition of viral DNA polymerase, pritelivir prevents de novo synthesis of virus DNA through inhibition of the helicase-primase complex. In addition, it does not require activation within an HSV infected cell by viral thymidine kinase and therefore, is also protective to uninfected cells.
With the context of the invention, similar expressions which all would denote the compound pritelivir are “BAY 57-1293”, “AIC090096” and “AIC316”.
Likewise, the terms ”pritelivir”, “BAY 57-1293”, “AIC090096” and “AIC316″ or the compound *’N-[5-(ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridm phenyl] -acetamide” would reflect throughout the text a compound having the structural formula:
Synthetic route – Manufacture of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-Yl]-N-methyl- 2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate
The starting materials (4-pyridine-2-yl-phenyl)-acetic acid (PP-acetic acid; C-023930) and aminothiazole sulfonic acid amide (C-023936) are coupled using standard reaction conditions
(N-Ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCl), tetrahydrofuran (THF)/N-methylpyrrolidone (NMP) to deliver N-[5-(aminosulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (C-023931). To obtain the hemihydrate, N-[5-(aminosulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate free base is recrystallized from THF/water. A flowchart showing the synthesis of N-[5-(aminosulfonyl)- 4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is provided in below in the reaction scheme below 1.
Description of the manufacturing process of N-r5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate
PP-acetic acid and aminothiazole sulfonic acid amide are mixed in THF/NMP, the mixture is cooled and then EDC x HCl is added in portions. The reaction mixture is stirred for several hours, and then added slowly to purified water. The suspension is stirred and filtered; the product cake is washed with purified water and dried at room temperature in a nitrogen stream and then under vacuum. Purified water is added slowly at elevated temperature, the suspension is stirred for several hours. The suspension is cooled to 5°C and stirred further for several hours. The product is isolated by filtration and washed with purified water. The product is dried at 65°C under vacuum until the criterion for water content is reached. A major advantage of the synthesis of free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate is the absence impurities related to the presence of mesylate ester that might be present in the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate.
PAPER
By: Carta, Fabrizio ; et al. Journal of Medicinal Chemistry (2017), 60(7), 3154-3164
SULPHURIC ACID FOR SULPHATE A SIMILAR REACTION BUT NOT SAME
PAPER
https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00668
Chemistry of Pritelivir
Synthesis of pritelivir and its analogues is based on the reported methods in the literature (18−20) and presented in Figure 4. A simple retrosynthetic disconnection of the target compound suggests a coupling of the thiazolyl sulfonamide and diaryl acetic acid (Figure 4a). During the course of development an optimized route applying the principles of green chemistry was developed and will be used for the commercial phase.
Figure 4. Synthesis of pritelivir (16) and analogues: (a) disconnection approach to target molecules; (b) synthesis of thiazolyl sulfonamide reagents; (c) synthesis of diaryl acetic acids; (d) synthesis of some representative examples of pritelivir and analogues. (18−20)
The synthesis of the thiazolyl sulfonamide reagents begins with a reaction of chloroacetone (17) and potassium thiocyanide to give an intermediate ketone which was cyclized to the thiazole 18 by treatment with gaseous hydrochloride (Figure 4b). Chlorosulfonylation with chlorosulfonic acid and thionyl chloride resulted in the sulfonyl chloride 19 that was converted to the corresponding sulfonamides 20 and 21 after treatment with ammonia or methylamine, respectively. The 2-chloro substituent in 20 and 21 was converted to the methyl amine in an SNAr reaction to deliver the building blocks 22–23. Diaryl acetic acid reagents were synthesized using palladium catalyzed coupling reactions with organometallic intermediates formed from the corresponding halo-aryl esters (Figure 4c). Ester saponification then delivered the corresponding carboxylic acids (e.g., 26 and 28, Figure 4c). Finally, the target molecules, for instance, 5, 11, 16, and 9, were obtained using amide coupling reaction conditions with corresponding diaryl acetic acids and the thiazolyl sulfonamides (Figure 4d). (18−20)
Medical use
Pritelivir is currently being developed for the treatment of immunocompromised patients with mucocutaneous HSV lesions that are resistant to acyclovir.
HSV in immunocompromised patients
Although HSV infection is very common in the general population, it rarely causes serious disease and is effectively contained by the immune system. In those with a weakened immune system such as transplant recipients, people receiving chemo- or radiotherapy, or HIV patients, an active HSV infection can cause disease in 35-68% of patients and may become severe or even life-threatening.[1]
Standard of care treatments
HSV treatment revolves around the use of nucleoside analogues (NA) which act via the viral DNA polymerase, causing DNA chain termination and prevention of viral replication. First-line treatment is generally acyclovir or its prodrug valacyclovir. Resistance to acyclovir is more common in HSV patients with weakened or suppressed immune systems, affecting between 4 and 25% of cases.[2][3][4][5][6]
Resistance to standard treatments
If HSV drug resistance is mediated by mutation(s) of the viral UL23 gene, which encodes the viral thymidine kinase (TK), then the pyrophosphate analogue foscarnet may be effective as a rescue treatment, since it does not require activation by TK. The use of foscarnet is commonly accompanied by restrictive toxicity, particularly nephrotoxicity.[7] If the virus also acquires resistance to foscarnet, then there is currently no FDA approved treatment.
Clinical research
Completed phase II clinical trials in otherwise healthy patients with genital herpes
- A Double-blind Randomized Placebo Controlled Dose-finding Trial to Investigate Different Doses of a New Antiviral Drug in Subjects With Genital HSV Type 2 Infection.[8][9]
- A Double-blind, Double Dummy, Randomized Crossover Trial to Compare the Effect of “AIC316 (Pritelivir)” 100 mg Once Daily Versus Valacyclovir 500 mg Once Daily on Genital HSV Shedding in HSV-2 Seropositive Adults.[10][11]
Ongoing phase II / phase III clinical trials with pritelivir
A phase II / III multinational, comparator-controlled, clinical trial in immunocompromised patients with acyclovir-resistant mucocutaneous lesions is listed on ClinicalTrials.gov[12] and EudraCT.[13]
Pharmacology
Mechanism of action
Pritelivir is a member of the helicase-primase inhibitors (HPI), a novel class of direct-acting antiviral drugs acting specifically against HSV-1 and HSV-2.[14][15] As the name suggests, the drugs act through inhibition of the viral helicase primase complex, encoded by the UL5 (helicase), UL8 (scaffold protein) and UL52 (primase) genes, which is essential for HSV replication.[16] The helicase primase complex is encoded separately from the viral DNA polymerase (encoded by the UL30 gene). Because HPIs i) do not target the viral DNA polymerase and ii) do not require activation by the viral thymidine kinase enzyme (encoded by the UL23 gene), mutations causing resistance to NAs are not protective against HPIs. Similarly, resistance to HPIs does not confer resistance to NAs.
References
- ^ Wilck, M.B.; Zuckerman, R.A.; A. S. T. Infectious Diseases Community of Practice (2013). “Herpes simplex virus in solid organ transplantation”. Am J Transplant. 13 (Suppl 4): 121–7. doi:10.1111/ajt.12105. PMID 23465005. S2CID 44969727.
- ^ Zuckerman, R.; Wald, A.; A. S. T. Infectious Diseases Community of Practice (2009). “Herpes simplex virus infections in solid organ transplant recipients”. Am J Transplant. 9 (Suppl 4): S104-7. doi:10.1111/j.1600-6143.2009.02900.x. PMID 20070669. S2CID 205846431.
- ^ Frobert, E.; Burrel, S.; Ducastelle-Lepretre, S.; Billaud, G.; Ader, F.; Casalegno, J.S. (2014). “Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France”. Antiviral Res. 111: 36–41. doi:10.1016/j.antiviral.2014.08.013. PMID 25218782.
- ^ Patel, D.; Marchaim, D.; Marcus, G.; Gayathri, R.; Lephart, P.R.; Lazarovitch, T.; Zaidenstein, R.; Chandrasekar, P. (2014). “Predictors and outcomes of acyclovir-resistant herpes simplex virus infection among hematopoietic cell transplant recipients: case-case-control investigation”. Clin Transplant. 28 (1): 1–5. doi:10.1111/ctr.12227. PMID 24033498. S2CID 37729458.
- ^ Danve-Szatanek, C.; Aymard, M.; Thouvenot, D.; Morfin, F.; Agius, G.; Bertin, I. (2004). “Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up”. J Clin Microbiol. 42 (1): 242–9. doi:10.1128/JCM.42.1.242-249.2004. PMC 321677. PMID 14715760.
- ^ Chakrabarti, R.; Pillay, D.; Ratcliffe, D.; Cane, P.A.; Collingham, K.E.; Milligan, D.W. (2000). “Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance”. J Infect Dis. 181 (6): 2055–8. doi:10.1086/315524. PMID 10837192.
- ^ SmPC
- ^ NCT01047540
- ^ Wald, A.; Timmler, B.; Magaret, A.; Warren, T.; Trying, S. (2014). “Helicase-primase inhibitor pritelivir for HSV-2 infection”. N Engl J Med. 370 (3): 201–10. doi:10.1056/NEJMoa1301150. PMID 24428466.
- ^ NCT01658826
- ^ Wald, A.; Timmler, B.; Warren, T.; Trying, S.; Johnston, C. (2016). “Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial”. JAMA. 316 (23): 2495–2503. doi:10.1001/jama.2016.18189. hdl:1805/14200. PMID 27997653.
- ^ NCT03073967
- ^ 2020-004940-27
- ^ Biswas, S.; Jennens, L.; Field, H.J. (2007). “Single amino acid substitutions in the HSV-1 helicase protein that confer resistance to the helicase-primase inhibitor BAY 57-1293 are associated with increased or decreased virus growth characteristics in tissue culture”. Arch Virol. 152 (8): 1489–500. doi:10.1007/s00705-007-0964-7. PMID 17404685. S2CID 23688945.
- ^ Field, H.J.; Biswas, S. (2011). “Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus”. Drug Resist Updat. 14 (1): 45–51. doi:10.1016/j.drup.2010.11.002. PMID 21183396.
- ^ Crute, J.J.; Tsurumi, T.; Zhu, L.A.; Weller, S.K.; Olivo, P.D.; Challberg, M.D. (1989). “Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products”. Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2186–2189. Bibcode:1989PNAS…86.2186C. doi:10.1073/pnas.86.7.2186. PMC 286876. PMID 2538835.
- [1]. Ligat G, et al. Identification of Amino Acids Essential for Viral Replication in the HCMV Helicase-PrimaseComplex. Front Microbiol. 2018 Oct 23;9:2483. [Content Brief][2]. Wald A, et al. Helicase-primase inhibitor Pritelivir for HSV-2 infection. N Engl J Med. 2014 Jan 16;370(3):201-10. [Content Brief][3]. Quenelle DC, et al. Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis. Antiviral Res. 2018 Jan;149:1-6. [Content Brief]
| Names | |
|---|---|
| Systematic IUPAC nameN-Methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide | |
| Identifiers | |
| CAS Number | 348086-71-5 |
| 3D model (JSmol) | Interactive image |
| ChemSpider | 430613 |
| KEGG | D12811 |
| PubChem CID | 491941 |
| UNII | 07HQ1TJ4JE |
| CompTox Dashboard (EPA) | DTXSID70188344 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C18H18N4O3S2 |
| Molar mass | 402.49 g·mol−1 |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references | |
///////////PRITELIVIR MESYLATE, AIC316 mesylate hydrate, BAY 57-1293 mesylate hydrate, AIC 316 mesylate hydrate, BAY 57-1293 mesylate hydrate, BAY57-1293, BAY 57-1293, BAY-57-1293, BAY571293, BAY 571293, BAY-571293, AIC-316, AIC 316
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PIMICOTINIB
PIMICOTINIB
CAS 2253123-16-7
ABSK021
WeightAverage: 420.473
Monoisotopic: 420.190988657
Chemical FormulaC22H24N6O3
3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide
CSF-1R inhibitor Pimicotinib (ABSK021) of Abbisko Therapeutics, HV1XI8HST2
Pimicotinib (ABSK021), an oral, highly potent and selective small molecule blocker of the colony-stimulating factor 1 receptor (CSF-1R) independently discovered by Abbisko Therapeutics. A number of studies have shown that blocking the CSF-1R signaling pathway could effectively modulate and change macrophage functions, and potentially treat many macrophage-dependent human diseases.[1]
Pimicotinib is under investigation in clinical trial NCT05804045 (Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER)).
History
In December 2023, Abbisko Therapeutics entered into a licensing agreement for pimicotinib in all indications for China rights with Merck KGaA.[2] [3][4]
In April 2023, a global phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the safety and efficacy of pimicotinib in patients with tenosynovial giant cell tumor was started (NCT05804045).[5]
Following with pimicotinib for tenosynovial giant cell tumor treatment in phase III, pimicotinib has also entered into a phase II trial in June 2023 for cGVHD treatment in China.[6]
The U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of NMPA granted pimicotinib breakthrough therapy designation (BTD) for the treatment of tenosynovial giant cell tumor patients that are not amenable to surgery in January 2023 and July 2022, respectively.[7]
Research
Pimicotinib is being investigated as a treatment for tenosynovial giant cell tumor,[8][9] chronic graft-versus-host-disease (cGVHD), and pancreatic cancer.
PATENTS
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214867&_cid=P10-MCTXKZ-70170-1
Example 41: Preparation of 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide
[0463]
[0464]Palladium carbon (50 mg) was added to a solution of 3-(benzyloxy)-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (80 mg, 0.15 mmol) in methanol (10 mL). The reaction was stirred at 50° C. for 2 hours in the presence of hydrogen. Filtered and concentrated. Plate chromatography (dichloromethane/methanol=18:1) gave 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (10 mg, yield 15%). MS m/z(ESI):423[M+1]
[0465]
1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.37(d,J＝5.7Hz,1H),8.27(s,1H),8.01–7.85(m,2H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝5.7,2.4Hz,1H),5.89(s,1H),3.86(s,3H),3.83–3.76(m,1H),3.67–3.61(m,1H),2.29(s,3H),2.09–1.98(m,2H),1.34(s,3H)。
PATENTS
EP3643715
WO2018233527
US20200140431
US11180495 WO2018233527 US20200140431
References
- ^ Vaynrub A, Healey JH, Tap W, Vaynrub M (2022). “Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations”. OncoTargets and Therapy. 15: 53–66. doi:10.2147/OTT.S345878. PMC 8763255. PMID 35046667.
- ^ Merck Strengthens Oncology Portfolio Through Commercialization Agreement With Abbisko for Phase III Asset, Pimicotinib. (2023) https://www.merckgroup.com/en/news/abbisko-pimicotinib-agreement-04-12-2023.html
- ^ Merck KGaA buys into Abbisko’s late-stage joint tumor med for $70M upfront. Fierce Biotech. (2023) https://www.fiercebiotech.com/biotech/merck-kgaa-buys-abbiskos-late-stage-joint-tumor-med-70m-upfront
- ^ “Abbisko Therapeutics Announced the Entry into a Licensing Agreement for Pimicotinib (ABSK021) with Merck”. http://www.prnewswire.com (Press release). Retrieved 18 April 2024.
- ^ Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER). U. S. National Institutes of Health, National Cancer Institute. https://classic.clinicaltrials.gov/ct2/show/NCT05804045
- ^ A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)U. S. National Institutes of Health, National Cancer Institute.https://classic.clinicaltrials.gov/ct2/show/NCT06186804
- ^ “FDA Grants Breakthrough Therapy Designation to Abbisko’s Pimicotinib”. Global genes. Retrieved 18 April 2024.
- ^ “Pimicotinib”. TGCT Support. Retrieved 18 April 2024.
- ^ “A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study of ABSK021 to Assess the Efficacy and Safety in Patients With Tenosynovial Giant Cell Tumor”. clinicaltrials. clinicaltrials.gov. 10 April 2024. Retrieved 18 April 2024.
External links
- “Pimicotinib”. NCI Drug Dictionary. National Cancer Institute.
- Clinical trial number NCT06186804 for “A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Other names | ABSK021 |
| Routes of administration | Oral |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2253123-16-7 |
| PubChem CID | 139549388 |
| ChemSpider | 128942304 |
| UNII | HV1XI8HST2 |
| KEGG | D12938 |
| Chemical and physical data | |
| Formula | C22H24N6O3 |
| Molar mass | 420.473 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Zhao BW, et al. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29.[2]. Yang S, et al. Abstract LB-288: A highly selective small molecule CSF-1R inhibitor demonstrates strong immunomodulatory activity in syngeneic models. Cancer Research, 2018, 78(13_Supplement): LB-288-LB-288.[3]. Zhang N, et al. Abstract LB077: CSF-1R inhibition with Pimicotinib (ABSK021) enhanced anti-tumor efficacy of KRASG12C inhibitors in preclinical non-small cell lung cancer mouse models. Cancer Research, 2024, 84(7_Supplement): LB077-LB077.
//////////PIMICOTINIB, ABSK 021, Abbisko Therapeutics, HV1XI8HST2
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PALTUSOTINE
PALTUSOTINE
CAS 2172870-89-0
- CRN00808
- F2IBD1GMD3
WeightAverage: 456.497
Monoisotopic: 456.17616767
Chemical FormulaC27H22F2N4O
3-[4-(4-Amino-1-piperidinyl)-3-(3,5-difluorophenyl)-6-quinolinyl]-2-hydroxybenzonitrile
fda 2025, approvals 2025, To treat acromegaly in adults who had an inadequate response to surgery and/or for whom surgery is not an option
- OriginatorCrinetics Pharmaceuticals
- ClassAmines; Antineoplastics; Antisecretories; Fluorobenzenes; Nitriles; Piperidines; Quinolines; Small molecules
- Mechanism of ActionSomatostatin receptor 2 agonists
- Orphan Drug Status – Acromegaly
- PreregistrationAcromegaly
- Phase IIMalignant carcinoid syndrome
- 08 May 2025Crinetics Pharmaceuticals expects potential EMA decision for paltusotine in Acromegaly, in the first half of 2026
- 08 May 2025FDA assigns PDUFA action date of 25/09/2025 for paltusotine for acromegaly
- 08 May 2025Crinetics Pharamceuticals plans the phase III CAREFNDR trial for Malignant carcinoid syndrome (PO), in the second quarter of 2025
Paltusotine is a selective somatostatin receptor type 2 (SST2) agonist in development by Crinetics Pharmaceuticals for the treatment of acromegaly and certain neuroendocrine tumors. It is a small molecule delivered orally.[1][2][3][4]
SCHEME
PAPER
https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00431
Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist
Step 2-1, preparation of [1-(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tertbutyl ester: To a DMSO solution of 6-bromo-3,4-dichloroquinoline (950 mg, 1 Eq, 3.43 mmol)
was added tert-butyl piperidin-4-ylcarbamate (841 mg, 98% Wt, 1.2 Eq, 4.12 mmol) and DIPEA
(1.19 g, 1.60 mL, 3 Eq, 10.3 mmol). The resulting mixture was heated at 60 °C for overnight.
The reaction crude was quenched with water, extracted with EtOAc, washed with brine,
concentrated and purified by silica gel chromatography to afford tert-butyl (1-(6-bromo-3-
chloroquinolin-4-yl)piperidin-4-yl)carbamate (0.95 g, 2.2 mmol, 63 %) as an off-white solid. 1H
NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.25 (d, J=5 Hz, 1H), 7.94 (d, J=10 Hz, 1H), 7.74 (d,
J=10 Hz, 1H), 4.61 (s, 1H), 3.76 (s, 1H), 3.51 (m, 2H), 3.37 (m, 2H), 2.13-2.15 (m, 2H), 1.73-
1.65 (m, 2H), 1.48 (s, 9H). MS [M+H]
+= 442.0.
Step 4-2, preparation of 1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-
quinolin-4-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester: To a THF (5.0 mL) solution of [1-
(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.0 mmol, 440
mg) and 2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
benzonitrile (1.4 eq., 1.4 mmol, 460 mg) was added PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and
KOAc (3.0 eq., 3.0 mmol, 300 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 80 °C for 1 h. LCMS analysis
showed about 50% of the starting material has been converted to the desired product. Additional
2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile
(1.4 eq., 1.4 mmol, 460 mg), PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and KOAc (3.0 eq., 3.0
mmol, 300 mg) were added and the resulting solution was heated at 80 °C for another 2 h. The
reaction solution was combined with silica gel and concentrated. The residue obtained was
purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 0.512 g
of the desired product as white solid. MS [M+H]
+= 567.6.
Step 4-3, preparation of {1-[6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-3-(3,5-difluorophenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester: To a dioxane (5 mL)
solution of (1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-quinolin-4-yl}-
piperidin-4-yl)-carbamic acid tert-butyl ester (0.5 mmol, 283 mg) was added Pd(amphos)Cl2 (0.1
eq., 0.05 mmol, 37 mg), 3, 5-difluorophenyl boronic acid (3.0 eq., 1.5 mmol, 250 mg) and
K2CO3 (4.0 eq., 2.0 mmol, 276 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 95 °C for 0.5 h and LCMS analysis
showed that starting material was completely consumed. The reaction solution was concentrated
with silica gel and purified by silica gel chromatography eluting with ethyl acetate/hexane
(0~50%) to give 0.170 g of the desired product as white solid. MS (M+H)+= 645.6.
Step 4-4, preparation of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile: to the dichloromethane (5.0 mL) solution of {1-[6-[3-cyano-2-(2-methoxyethoxymethoxy)-phenyl]-3-(3,5-difluoro-phenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid
tert-butyl ester (0.264 mmol, 170 mg) was added trifluroroacetic acid (2.0 mL) and the resulting
mixture was stirred at ambient temperature for 2 h. The reaction solution was concentrated and
purified by C18 reversed phase chromatography eluting with MeCN/water (0~40%). Pure
fractions were combined, neutralized with saturated NaHCO3, extracted with ethyl acetate and
dried with MgSO4. The organic solution was concentrated with HCl in ether (2.0 M) to give the
final compound as HCl salt (68 mg, 0.138 mmol, 52%).
1H NMR (500 MHz, DMSO-d6) δ 10.77
(br s, 1H), 8.78 (s, 1H), 8.29-8.15 (m, 5H), 7.79 (dd, J=20 Hz, 5 Hz, 2H), 7.41 (m, 1H), 7.26-
7.19 (m, 3H), 3.59 (t, J=12 Hz, 2H), 3.31 (m, 1H), 3.00 (t, J=12 Hz, 2H), 2.05-1.99 (m, 2H),
1.76-1.74 (m, 2H). MS [M+H]
+= 457.5. 13C NMR (DMSO-d6) δ 30.2, 47.4, 50.8, 102.4, 103.2,
113.4, 117.2, 121.4, 124.6, 130.7, 133.1, 134.6, 136.0, 141.7, 156.6, 161.2, 163.2. LCMS purity
98% (254&220 nM). HRMS m/z [M+H]+ Calcd for C27H23F2N4O 457.1834; found 457.1833.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US235548187&_cid=P20-MCSHXW-73235-1
PATENTS
WO2021011641
WO2018013676
References
- ^ Madan, Ajay; Markison, Stacy; Betz, Stephen F.; Krasner, Alan; Luo, Rosa; Jochelson, Theresa; Lickliter, Jason; Struthers, R. Scott (April 2022). “Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers”. Pituitary. 25 (2): 328–339. doi:10.1007/s11102-021-01201-z. PMC 8894159. PMID 35000098.
- ^ Zhao, Jian; Wang, Shimiao; Markison, Stacy; Kim, Sun Hee; Han, Sangdon; Chen, Mi; Kusnetzow, Ana Karin; Rico-Bautista, Elizabeth; Johns, Michael; Luo, Rosa; Struthers, R. Scott; Madan, Ajay; Zhu, Yunfei; Betz, Stephen F. (12 January 2023). “Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist”. ACS Medicinal Chemistry Letters. 14 (1): 66–74. doi:10.1021/acsmedchemlett.2c00431. PMC 9841592. PMID 36655128.
- ^ Gadelha, Monica R; Gordon, Murray B; Doknic, Mirjana; Mezősi, Emese; Tóth, Miklós; Randeva, Harpal; Marmon, Tonya; Jochelson, Theresa; Luo, Rosa; Monahan, Michael; Madan, Ajay; Ferrara-Cook, Christine; Struthers, R Scott; Krasner, Alan (13 April 2023). “ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly”. The Journal of Clinical Endocrinology & Metabolism. 108 (5): e148 – e159. doi:10.1210/clinem/dgac643. PMC 10099171. PMID 36353760. S2CID 253445337.
- ^ Zhao, Jie; Fu, Hong; Yu, Jingjing; Hong, Weiqi; Tian, Xiaowen; Qi, Jieyu; Sun, Suyue; Zhao, Chang; Wu, Chao; Xu, Zheng; Cheng, Lin; Chai, Renjie; Yan, Wei; Wei, Xiawei; Shao, Zhenhua (21 February 2023). “Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine”. Nature Communications. 14 (1): 962. Bibcode:2023NatCo..14..962Z. doi:10.1038/s41467-023-36673-z. ISSN 2041-1723. PMC 9944328. PMID 36810324.
| Legal status | |
|---|---|
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2172870-89-0 |
| PubChem CID | 134168328 |
| ChemSpider | 81367268 |
| UNII | F2IBD1GMD3 |
| Chemical and physical data | |
| Formula | C27H22F2N4O |
| Molar mass | 456.497 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
////////PALTUSOTINE, ORPHAN DRUG, Acromegaly, CRN 00808, F2IBD1GMD3, fda 2025, approvals 2025
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PALAZESTRANT
PALAZESTRANT
CAS 2092925-89-6
OP-1250, VU35KM56Q4
449.6 g/mol, C28H36FN3O
(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole
- (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole
- (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-{4-[(1-propylazetidin-3- yl)oxy]phenyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Palazestrant (OP-1250) is an investigational drug being developed for estrogen receptor-positive (ER+) breast cancer. It is a small molecule with a dual mechanism of action, acting as both a complete estrogen receptor antagonist and a selective estrogen receptor degrader (SERD). This means it can block estrogen receptor activity and also degrade the receptor itself, potentially offering a more effective treatment approach.
Here’s a more detailed breakdown:
- Dual Mechanism:Palazestrant is a complete ER antagonist, meaning it blocks all estrogen receptor activity. It is also a SERD, which means it degrades the estrogen receptor, preventing it from functioning.
- Oral Administration:Palazestrant is an orally available drug.
- Clinical Trials:Palazestrant is currently in clinical trials, including Phase 1/2 and Phase 3 studies, for the treatment of ER+, HER2- metastatic breast cancer.
- Combination Therapy:Palazestrant is being evaluated in combination with other drugs like CDK4/6 inhibitors (e.g., ribociclib).
- Promising Results:Preliminary results from clinical trials have shown promising antitumor efficacy and favorable pharmacokinetic properties for palazestrant.
- FDA Fast Track Designation:The FDA has granted Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following endocrine therapy with a CDK4/6 inhibitor.
- Brain Metastasis:Palazestrant has shown activity in brain metastasis animal models.
- ESR1 Mutation Status:Palazestrant has demonstrated activity against both wild-type and mutant ER (ESR1) breast cancer models.
Palazestrant is an investigational new drug which is being evaluated for the treatment of estrogen receptor-positive (ER+) breast cancer, with a dual mechanism of action as both a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD). This orally bioavailable small molecule has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor.[1]
SCHEME
MAIN
PAPER
https://pubs.acs.org/doi/10.1021/acsomega.4c11023
PATENTS
https://patentscope.wipo.int/search/en/detail.jsf?docId=US379744130&_cid=P22-MCPZ5L-11621-1
PATENTS’
WO2017059139
WO2023225354
WO2023091550
WO2023283329
WO2021178846
References
- ^ Parisian AD, Barratt SA, Hodges-Gallagher L, Ortega FE, Peña G, Sapugay J, et al. (March 2024). “Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination”. Molecular Cancer Therapeutics. 23 (3): 285–300. doi:10.1158/1535-7163.MCT-23-0351. PMC 10911704. PMID 38102750.
| Clinical data | |
|---|---|
| Other names | OP-1250 |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2092925-89-6 |
| PubChem CID | 135351887 |
| DrugBank | DB18971 |
| ChemSpider | 128922074 |
| UNII | VU35KM56Q4 |
| KEGG | D12827 |
| ChEMBL | ChEMBL5314475 |
| Chemical and physical data | |
| Formula | C28H36FN3O |
| Molar mass | 449.614 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
///////////PALAZESTRANT, OP 1250, A1AEA, VU35KM56Q4
Orforglipron’
Orforglipron’
CAS 2212020-52-3
C48H48F2N10O5
883.0 g/mol MW
LY-3502970
- OWL833
- 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
- 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
SCHEME
PATENT
JP2019099571
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018056453&_cid=P22-MCLODW-73083-1
<Example Compound 67>
Main cycle isomer
1 H-NMR (600 MHz, CDCl
3 ) δ: 11.32 (1H, s), 8.13 (1H, d, J
ＨＦ＝0.7 Hz), 7.59 (1H, d, J ＝8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J ＝8.9 Hz, J
ＨＦ ＝6.9 Hz ), 7.28 (1H, d, J ＝8.9 Hz), 7.26 (1H, dd, J ＝8.6, 1.7 Hz), 7.16 (2H, d, J
ＨＦ =6.1Hz), 6.70 (1H, s), 6.61 (1H, dd, J = 3.0Hz,
JHF =1.1Hz), 6.31 (1H, d, J = 3.0Hz), 5.79 (1H, q, J = 6.7Hz), 4.4 7 (1H, dd, J=13.5, 5.2Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1 H, m), 3.60 (1H, ddd, J = 13.5, 12.9, 3.6Hz), 3.15 (1H, ddd, J = 15.8, 12.9, 5.2Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J
HF =1.1Hz), 1.91 (1H, dd, J = 6.1, 5.8Hz), 1.79-1.76 ( 2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8Hz ), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0Hz).
[0437] Parainversion isomer
1 H-NMR (600 MHz, CDCl
3 ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 7.06 (2H, d, J
HF =6.0Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 ( 1H, d, J=3.0Hz), 5.26 (1H, q, J=6.6Hz), 4. 87 (1H, dd, J = 13.1, 4.8Hz), 4.07 (3H, s), 3 .90-3.80 (2H, m), 3.39 (1H, ddd, J = 13.1, 1 2.2, 4.6Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6H z), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 ( 3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0Hz).
Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.[1]
Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.[2]
Mechanism
Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.[1][3]
Clinical trials
The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.[4][5]
Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.[3]
Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.[1][6]
The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]
Phase III ACHIEVE-1 trial
In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.[1][7]
More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[1][8]
Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[1]
References
- ^ Jump up to:a b c d e f g h “Lilly’s oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial” (Press release). Eli Lilly. April 17, 2025. Retrieved April 18, 2025.
- ^ Sidik S (2023). “Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective”. Nature. 619 (7968): 19. Bibcode:2023Natur.619…19S. doi:10.1038/d41586-023-02092-9. PMID 37369789.
- ^ Jump up to:a b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). “Emerging pharmacotherapies for obesity: A systematic review”. Pharmacological Reviews. 77 (1): 100002. doi:10.1124/pharmrev.123.001045. PMID 39952695.
- ^ Pratt E, Ma X, Liu R, et al. (June 2023). “Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes”. Diabetes, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
- ^ Wharton S, Blevins T, Connery L, et al. (June 2023). “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity”. The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
- ^ Jump up to:a b c Frias J, et al. (2023). “Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study”. The Lancet. 402 (10400): 472–83.
- ^ Constantino AK (April 17, 2025). “Eli Lilly’s weight loss pill succeeds in first late-stage trial on diabetes patients”. CNBC. Retrieved April 17, 2025.
- ^ Kolata G (April 17, 2025). “Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar”. The New York Times. ISSN 0362-4331. Retrieved April 17, 2025.
External links
- What to Know About Eli Lilly’s Daily Pill for Weight Loss, The New York Times, April 17, 2025
| Above: molecular structure of orforglipron Below: 3D representation of an orforglipron molecule | |
| Clinical data | |
|---|---|
| Other names | LY-3502970 |
| Routes of administration | Oral |
| ATC code | None |
| Pharmacokinetic data | |
| Elimination half-life | 29–49 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2212020-52-3 |
| PubChem CID | 137319706 |
| ChemSpider | 71117507 |
| UNII | 7ZW40D021M |
| ChEMBL | ChEMBL4446782 |
| Chemical and physical data | |
| Formula | C48H48F2N10O5 |
| Molar mass | 882.974 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
///////////Orforglipron, LY-3502970, LY 3502970, OWL833, OWL 833
Taletrectinib
Taletrectinib
CAS 1505514-27-1
as salt: 1505515-69-4, Taletrectinib adipate
FDA 6/11/2025, Ibtrozi, To treat locally advanced or metastatic ROS1-positive non-small cell lung cancer ALSO CHINA 2024 APPROVED |
405.5 g/mol, C23H24FN5O, UNII-W4141180YD
3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine
Taletrectinib adipate
WeightAverage: 551.619
Monoisotopic: 551.254397378
Chemical FormulaC29H34FN5O5
DS-6051B, CAS 1505515-69-4,
6KLL51GNBG, 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine; hexanedioic acid
Taletrectinib, sold under the brand name Ibtrozi, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[1][2] It is used as the salt, taletrectinib adipate.[1] Taletrectinib is a kinase inhibitor.[1] It is taken by mouth.[1]
Taletrectinib was approved for medical use in the United States in June 2025.[3]
SYN
US20200062765
https://patentscope.wipo.int/search/en/detail.jsf?docId=US289038418&_cid=P12-MCIHV1-02369-1
Example 1
tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)
Example 2
6-Fluoroimidazo[1,2-b]pyridazine methanesulfonate (2)
Example 3
tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)
Example 4
tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)
Example 5
3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023272701&_cid=P12-MCIHPU-95869-1
The NMR data for the crystalline form A of Compound 1 adipate are as follows: 1H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H) , 1.47-1.48 (d, J=5.0 Hz, 7H) , 2.15-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H) , 3.25-3.29 (m, 1H) , 3.79-3.83 (m, 2H) , 4.80-4.85 (m, 1H) , 6.76-6.77 (d, J=5.0 Hz, 1H) , 6.92-6.94 (d, J=10.0 Hz, 2H) , 7.01-7.05 (t, J=10.0 Hz, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.64-7.65 (d, J=5.0 Hz, 1H) , 7.72-7.76 (t, J=10.0 Hz, 4H) .
[0148]
The IR data for the crystalline form A of Compound 1 adipate are as follows: IR (cm -1) : 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.
Example 5: Preparation and Characterization of Crystalline Form A of Compound 1 Free Base
[0212]
Compound 1 HCl (75.5 g) (e.g., obtained by using the method described in Example 5 of U.S. Application Publication No. 2020/0062765) was dissolved in ethanol (604 mL) at 50℃. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1℃ in 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the solid thus obtained was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The solid thus obtained was confirmed to be the crystalline form A of Compound 1 free base.
[0213]
The NMR data for the crystalline form A of Compound 1 free base are as follows: 1H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H) , 1.48-1.49 (d, J=5.0 Hz, 3H) , 3.16-3.20 (m, 1H) , 3.75-3.79 (m, 2H) , 4.82-4.86 (m, 1H) , 6.76-6.78 (d, J=10.0 Hz, 1H) , 6.92-6.94 (m, 2H) , 7.01-7.05 (m, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.62-7.63 (d, J=5.0 Hz, 1H) , 7.72-7.75 (m, 4H) .
[0214]
The IR data for the crystalline form A of Compound 1 free base are as follows: IR (cm -1) : 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Taletrectinib is an oral, next-generation ROS1 TKI developed by Nuvation Bio Inc. for the treatment of ROS1-positive NSCLC. In 2024, the NMPA approved taletrectinib for adult patients with locally advanced or metastatic ROS1-positive NSCLC, regardless of prior ROS1TKI treatment [47]. Under an exclusive license agreement, Innovent Biologics will commercialize taletrectinib in China under the brand
name DOVBLERON®. Taletrectinib exerts its pharmacological action through the mechanism of selectively impeding the ROS1 receptor tyrosine kinase, which effectively disrupts the signaling cascades which are responsible for facilitating the growth and survival of cancer cells in ROS1-positive NSCLC. This inhibition of the ROS1 receptor tyrosine kinase is a key event in the drug’s mode of action, as it specifically targets the molecular processes that drive the progression of the disease in ROS1-positive NSCLC cases [48]. The NMPA granted approval founded on the data sourced from the crucial Phase 2 TRUST – I study. This study substantiated that patients administered with taletrectinib achieved sustained responses and extended PFS. Regarding safety, taletrectinib boasted a generally good tolerability. It presented an advantageous safety profile and favorable tolerability characteristics, as evidenced by the low incidences of dose reduction and treatment discontinuation triggered by adverse effects. [49]. Overall, taletrectinib represents a promising therapeutic option for patients with advanced ROS1-positive NSCLC, offering efficacy in both TKI-naïve and TKI-pretreated populations, including those with CNS metastases [50–52].
The synthesis of Taletrectinib, illustrated in Scheme 12, commences with Mitsunobu coupling of Tale-001 and Tale-002 to afford Tale-003, which then undergoes Suzuki coupling with Tale-004 constructing
Tale-005 [53]. Sequential acidolysis/deprotection of Tale-005 ultimately delivers Taletrectinib
[47] M. P´ erol, N. Yang, C.M. Choi, Y. Ohe, S. Sugawara, N. Yanagitani, G. Liu, F.G.M.
D. Braud, J. Nieva, M. Nagasaka, 1373P efficacy and safety of taletrectinib in
patients (pts) with ROS1+ non-small cell lung cancer (NSCLC): interim analysis of
global TRUST-II study, Ann. Oncol. 34 (2023) S788–S789.
[48] G. Harada, F.C. Santini, C. Wilhelm, A. Drilon, NTRK fusions in lung cancer: from
biology to therapy, Lung Cancer 161 (2021) 108–113.
[49] W. Li, A. Xiong, N. Yang, H. Fan, Q. Yu, Y. Zhao, Y. Wang, X. Meng, J. Wu, Z. Wang,
Y. Liu, X. Wang, X. Qin, K. Lu, W. Zhuang, Y. Ren, X. Zhang, B. Yan, C.M. Lovly,
C. Zhou, Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non-
small cell lung cancer: the phase II TRUST-I study, J. Clin. Oncol. 42 (2024)
2660–2670.
[50] M. Nagasaka, D. Brazel, S.I. Ou, Taletrectinib for the treatment of ROS-1 positive
non-small cell lung cancer: a drug evaluation of phase I and II data, Expert Opin
Investig Drugs 33 (2024) 79–84.
[51] S. Waliany, J.J. Lin, Taletrectinib: TRUST in the continued evolution of treatments
for ROS1 fusion-positive lung cancer, J. Clin. Oncol. 42 (2024) 2622–2627.
[52] M. Nagasaka, Y. Ohe, C. Zhou, C.M. Choi, N. Yang, G. Liu, E. Felip, M. P´ erol,
B. Besse, J. Nieva, L. Raez, N.A. Pennell, A. Dimou, F. Marinis, F. Ciardiello,
T. Seto, Z. Hu, M. Pan, W. Wang, S. Li, S.I. Ou, TRUST-II: a global phase II study of
taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors,
Future Oncol. 19 (2023) 123–135.
[53] Y. Takeda, K. Yoshikawa, Y. Kagoshima, Y. Yamamoto, R. Tanaka, Y. Tominaga,
M. Kiga, Y. Hamada, Preparation of imidazo[1,2-b]pyridazine Derivatives as
Potent Inhibitors of ROS1 Kinase and NTRK Kinase, 2013. WO2013183578A1.
Medical uses
Taletrectinib is indicated for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer.[1][2]
Adverse effects
The FDA prescribing information for taletrectinib includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.[1][3]
History
The efficacy of taletrectinib to treat ROS1-positive non-small cell lung cancer was evaluated in participants with locally advanced or metastatic, ROS1-positive non-small cell lung cancer enrolled in two multi-center, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811).[3] The efficacy population included 157 participants (103 in TRUST-I; 54 in TRUST-II) who were naïve to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 participants (66 in TRUST-I; 47 in TRUST-II) who had received one prior ROS1 tyrosine kinase inhibitor.[3] Participants may have received prior chemotherapy for advanced disease.[3] The US Food and Drug Administration (FDA) granted the application for taletrectinib priority review, breakthrough therapy, and orphan drug designations.[3]
Society and culture
Legal status
Taletrectinib was approved for medical use in the United States in June 2025.[3][4]
Names
Taletrectinib is the international nonproprietary name.[5]
Taletrectinib is sold under the brand name Ibtrozi.[3][4]
References
- ^ Jump up to:a b c d e f g “Prescribing Information for NDA 219713, Supplement 000” (PDF). Drugs@FDA. U.S. Food and Drug Administration. April 2025. Retrieved 14 June 2025.
- ^ Jump up to:a b Khan I, Sahar A, Numra S, Saha N, Nidhi, Parveen R (April 2025). “Efficacy and safety of taletrectinib for treatment of ROS1 positive non-small cell lung cancer: A systematic review”. Expert Opinion on Pharmacotherapy. 26 (6): 765–772. doi:10.1080/14656566.2025.2487150. PMID 40170301.
- ^ Jump up to:a b c d e f g h “FDA approves taletrectinib for ROS1-positive non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 11 June 2025. Retrieved 13 June 2025.
This article incorporates text from this source, which is in the public domain. - ^ Jump up to:a b “U.S. Food and Drug Administration Approves Nuvation Bio’s Ibtrozi (taletrectinib), a Next-Generation Oral Treatment for Advanced ROS1-Positive Non-Small Cell Lung Cancer”. Nuvation Bio (Press release). 12 June 2025. Retrieved 13 June 2025.
- ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.
External links
- Clinical trial number NCT04395677 for “A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene” at ClinicalTrials.gov
- Clinical trial number NCT04919811 for “Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC (TRUST-II)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Ibtrozi |
| License data | US DailyMed: Taletrectinib |
| Routes of administration | By mouth |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 1505514-27-1as salt: 1505515-69-4 |
| PubChem CID | 72202474as salt: 72694302 |
| DrugBank | DB18711 |
| ChemSpider | 114934673as salt: 88297530 |
| UNII | W4141180YDas salt: 6KLL51GNBG |
| KEGG | D12363as salt: D12364 |
| ChEMBL | ChEMBL4650989as salt: ChEMBL4650361 |
| Chemical and physical data | |
| Formula | C23H24FN5O |
| Molar mass | 405.477 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
/////////Taletrectinib, FDA 2025, APPROVALS 2025, Ibtrozi, CANCER, AB-106, DS-6051a, UNII-W4141180YD, DS 6051B, APPROVALS 2024, CHINA 2024, Nuvation Bio Inc
Olgotrelvir
Olgotrelvir
STI-1558, HY-156655, CS-0887294, STI 1558, HY 156655, CS 0887294
Cas 2763596-71-8
494.6 g/mol, C22H30N4O7S, ZP3BDH359D
C22H30N4O7S 3-Pyrrolidinepropaney, α-hydroxy-β-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, (βS,3S)-
- (2S)-2-[(S)-2-(1H-Indole-2-carboxamido)-4-methylpentanamido]-1-hydroxy-3-[(S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
- 3-Pyrrolidinepropanesulfonic acid, alpha-hydroxy-beta-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, (betaS,3S)-
Olgotrelvir sodium, C22H30N4O7S.Na, CAS 2763596-71-8
3-Pyrrolidinepropanesulfonic acid, α-hydroxy-β-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, sodium salt (1:1), (βS,3S)-
Olgotrelvir (STI-1558) is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting the SARS-CoV-2 main protease (Mpro), a key enzyme that SARS-CoV-2 needs to replicate,[1][2][3][4] and by blocking viral entry.[2][5]
SCHEME
Main
PATENT
US20230322668 – PROTEASE INHIBITORS AS ANTIVIRALS
Example S1: Synthesis of Compounds A-1-a, A-1-b, A-1-c and A-1-d
US20230026438 – PROTEASE INHIBITORS AS ANTIVIRALS
WO2022256434 – PROTEASE INHIBITORS AS ANTIVIRALS
Example S1: Synthesis of Compounds A-1-a, A-1-b, A-1-c and A-1-d
[00224] To a dichloromethane (2.5 L) solution of 1H-indole-2-carboxylic acid (compound 101) (200 g, 1.24 mol) and N-hydroxy succinimide (157.1 g, 1.37 mol) was added EDCI (286 g, 1.49 mmol) at 0℃. After stirring at room temperature overnight, the solvent was removed under reduced pressure. The resulting solid was triturated with deionized water, and the solid was collected and dried under reduced pressure to give the compound 102 as a light-brown solid (310 g, 96%).
1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 – 7.35 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 2.92 (s, 4H).
[00225] To a stirred mixture of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-2- oxopyrrolidin-3-yl]-propanoate (compound 103) (500 g, 1748.24 mmol) in MeOH (200 mL) was
added 4M HCl in 1,4-dioxane (2000 mL) at room temperature. The mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride salt (compound 104) (389 g, 1721 mmol, 98%) as a light-yellow solid, which was used for next step without further purification. LCMS= [M+H]+: 187.1.
[00226] To a stirred mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride (389 g, 1721 mmol) (compound 104) and DIEA (866.162 mL, 5240.94 mmol) in DCM (1800 mL) and EtOH (500 mL) was added 2,5-dioxopyrrolidin-1-yl (2R)-2-{[(tert-butoxy)carbonyl]amino}-4-methyl-pentanoate (compound 105) (573.66 g, 1746.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated completion of the reaction. The reaction mixture was successively washed with water (1.0 L x 2), 0.5 M HCl (1.1 L), sat. NaHCO3 (1 L) and water (1 L). The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the compound 106 (700 g, 1752.23 mmol, >99%) as a light-yellow solid, which was used for next step without further purification. LCMS = [M+H]+: 400.3.
(400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.40 – 4.28 (m, 1H), 3.94 (dd, J = 15.1, 8.1 Hz, 1H), 3.74 – 3.52 (m, 3H), 3.15 (t, J = 8.8 Hz, 1H), 3.06 (dd, J = 16.4, 9.2 Hz, 1H), 2.33 (t, J = 9.2 Hz, 1H), 2.14 – 2.00 (m, 2H), 1.68 – 1.51 (m, 3H), 1.42 – 1.34 (m, 11H), 0.87 (dd, J = 11.4, 6.6 Hz, 6H).
[00227] A mixture of methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 106) (590 g, 1476.88 mmol) in HCl/dioxane (3 L) was stirred at room temperature for 2 h. LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to give compound 107 as a yellow solid (490 g, 99%), which was used for next step without further purification.
LCMS = [M+H]+: 300.2.
[00228] To a stirred mixture of methyl (S)-2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (compound 107) (418 g, 1235 mmol) and TEA (519.020 mL, 3734.03 mmol) in DMF (2500 mL) at room temperature was added 2,5-dioxopyrrolidin-1-yl 1H-indole-2-carboxylate (compound 102) (353 g, 1369.15 mmol) . The reaction mixture was stirred for 1.5 h. LCMS indicated that the reaction was complete. EtOAc (6 L) was added into the reaction mixture, which was then washed with brine (6 L x 6). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated down under reduced
pressure. Compound A-1-a was obtained as an off-white solid (414 g. Y: 76%), which was used for next step without further purification. LCMS = [M+H]+: 443.3. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.54 (t, J = 12.2 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 10.3 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 4.65 – 4.50 (m, 1H), 4.44 – 4.28 (m, 1H), 3.72 – 3.55 (s, 3H), 3.19 – 3.06 (m, 2H), 2.36 (ddd, J = 13.8, 10.3, 4.0 Hz, 1H), 2.16 – 2.03 (m, 2H), 1.79 – 1.49 (m, 5H), 0.92 (dt, J = 14.4, 7.2 Hz, 6H).
[00229] To a stirred solution of methyl (S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound A-1-a) (500 g, 1131 mmol) in THF (20 L) LiBH4 (74 g, 3393 mmol) was added portionwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 h. After reaction was completed (monitored by LCMS), the reaction mixture was quenched with sat. aqueous NH4Cl until no more gas formed. The mixture was washed with brine (5 L x 4), organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated down in vacuum. The resulting residue was purified by silica column chromatography (DCM : MeOH = 15 : 1) to give the desired product compound A-1-b (310 g, 66%) as a white solid. LCMS = [M+H]+: 415.2.
NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.50 (td, J = 9.7, 5.0 Hz, 1H), 3.80 (s, 1H), 3.40 – 3.28 (m, 1H), 3.28 – 3.20 (m, 1H), 3.15 – 2.99 (m, 2H), 2.33 – 2.20 (m, 1H), 2.12 (dt, J = 17.8, 9.4 Hz, 1H), 1.86 – 1.75 (m, 1H), 1.75 – 1.64 (m, 2H), 1.56 (ddd, J = 19.3, 9.6, 6.9 Hz, 2H), 1.45 – 1.35 (m, 1H), 0.91 (dd, J = 15.6, 6.3 Hz, 6H).
[00230] To a stirred solution of N-((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide (compound A-1-b) (8.3 g, 20 mmol) in DMSO (60 mL) was added 2-iodoxybenzoic acid (IBX) (11.2 g, 40 mmol) at room temperature. The reaction mixture was stirred at 30 ℃ for 18 h, and LCMS indicated completion of the reaction. The reaction mixture was diluted with EtOAc (300 mL) and filtered. The filtrate was washed with mixture of brine and sat. aqueous NaHCO3 (1:1 to 5:1, 200 mL x 5). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated down at rt to afford crude product. THF (40 mL) was added, and the mixture was stirred overnight at room temperature. The resulting solid was collected and dried under vacuum to yield the desired product N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)-propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) as a white solid (2.5 g, 31%). LCMS = [M+H]+:
413.2. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.64 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.14-7.05 (m, 2H), 7.01 (s, 1H), 6.34 (s, 1H), 4.90 (s, 1H), 4.34 (s, 1H), 3.27–3.22 (m, 2H), 2.43 (s, 1H), 2.30 (s, 1H), 2.01-1.96 (m, 1H), 1.94-1.91 (m, 1H) 1.88 – 1.65 (m, 4H), 1.00-0.98 (m, 6H).
[00231] To a stirred solution of N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) (31 g, 75.25 mmol) in EtOAc (300 mL) at room temperature was added a solution of NaHSO3 (27.56 mg, 72.73 mmol) in water (100 mL). The reaction mixture was heated at 50 ℃ for 3 h. After completion of reaction (monitored by LCMS), the organic layer was separated and removed. The aqueous layer was washed with EtOAc (100 mL x 5), concentrated down to remove remaining EtOAc, and then lyophilized to provide the desired product sodium (2S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (compound A-1-d) as off-white solid (32 g, 85%). LCMS = [M-Na+2H]+: 495.2. 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.45 (dd, J = 20.7, 8.2 Hz, 1H), 7.72 (dd, J = 48.9, 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.25 (dd, J = 5.1, 1.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.43 (dd, J = 50.7, 5.9 Hz, 1H), 4.57 – 4.41 (m, 1H), 4.33 – 4.03 (m, 1H), 4.01 – 3.82 (m, 1H), 3.19 – 2.92 (m, 2H), 2.29 – 2.08 (m, 2H), 2.06 – 1.90 (m, 1H), 1.83 – 1.51 (m, 5H), 1.00 – 0.83 (m, 6H).
PAPER
https://www.sciencedirect.com/science/article/pii/S2666634023004026
Mechanism of action
Olgotrelvir is a prodrug that first converts to its active form, AC1115.[2][5] AC1115 is believed to work by inhibiting the SARS-CoV-2 main protease (also known as 3C-like protease). This protein is a crucial enzyme responsible for cleaving viral polyproteins into functional subunits essential for viral replication. By binding to the active site of the protease, the drug prevents this cleavage process, effectively halting viral assembly and impeding the virus’s ability to produce future virions.[1][2][3][5]
Olgotrelvir also appears to inhibit cathepsin L (CTSL),[2][5] a protein implicated in facilitating viral entry of SARS-CoV-2 into the host cell.[2][5][6]
Clinical trials
In September 2023, the drug’s developer, Sorrento Therapeutics, announced top-line data that olgotrelvir had met its primary endpoints in a phase III clinical trial that enrolled 1,212 patients with mild or moderate COVID-19. The drug appeared to shorten the recovery time of 11 COVID-19 symptoms in olgotrelvir-treated patients by 2.4 days on average compared to patients in the placebo group. The drug was also shown to reduce the viral load at day 4 in treated patients compared to the placebo group. Side effects were mostly mild and infrequent, with the most common being nausea (1.5% vs. 0.2%) and skin rash (3.3% vs. 0.3%), which occurred more often in the olgotrelvir group.[7][8][9]
References
- ^ Jump up to:a b Tong X, Keung W, Arnold LD, Stevens LJ, Pruijssers AJ, Kook S, et al. (November 2023). “Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions”. Antimicrobial Agents and Chemotherapy. 67 (11): e0084023. doi:10.1128/aac.00840-23. PMC 10649086. PMID 37800975.
Other examples of Mpro inhibitors in late-stage development include STI-1558, currently in the phase 3 clinical trial in adult subjects with mild or moderate COVID-19 (NCT05716425).
- ^ Jump up to:a b c d e f Hackett DW (26 June 2023). “Second Generation Oral Mpro Inhibitor for COVID-19 Treatment Proceeds in Phase 3 Study”. Precision Vaccinations. Retrieved 27 December 2023.
- ^ Jump up to:a b “Coronavirus disease 2019 (COVID-19) emerging treatments”. BMJ Best Practice US. Archived from the original on 27 December 2023. Retrieved 27 December 2023.
- ^ Janin YL (September 2023). “On the origins of SARS-CoV-2 main protease inhibitors”. RSC Medicinal Chemistry. 15 (1): 81–118. doi:10.1039/D3MD00493G. ISSN 2632-8682. PMC 10809347. PMID 38283212. S2CID 264103864.
- ^ Jump up to:a b c d e Mao L, Shaabani N, Zhang X, Jin C, Xu W, Argent C, et al. (January 2024). “Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19”. Med (New York, N.Y.). 5 (1): 42–61.e23. doi:10.1016/j.medj.2023.12.004. PMID 38181791.
- ^ Berdowska I, Matusiewicz M (October 2021). “Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract”. World Journal of Gastroenterology. 27 (39): 6590–6600. doi:10.3748/wjg.v27.i39.6590. PMC 8554394. PMID 34754154.
- ^ Jiang R, Han B, Xu W, Zhang X, Peng C, Dang Q, et al. (June 2024). “Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19”. NEJM Evidence. 3 (6): EVIDoa2400026. doi:10.1056/EVIDoa2400026. PMID 38804790.
- ^ Sherman AC, Baden LR (June 2024). “How To Measure Benefit in a Changing Pandemic – Olgotrelvir for SARS-CoV-2”. NEJM Evidence. 3 (6): EVIDe2400144. doi:10.1056/EVIDe2400144. PMID 38804789.
- ^ “Sorrento Announces Phase 3 Trial Met Primary Endpoint and Key Secondary Endpoint in Mild or Moderate COVID-19 Adult Patients Treated with Ovydso (Olgotrelvir), an Oral Mpro Inhibitor as a Standalone Treatment for COVID-19” (Press release). BioSpace. 12 September 2023. Retrieved 27 December 2023.
| Clinical data | |
|---|---|
| Trade names | Ovydso |
| Other names | STI-1558, HY-156655, CS-0887294 |
| Routes of administration | By mouth |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2763596-71-8 |
| PubChem CID | 166157331 |
| UNII | ZP3BDH359D |
| KEGG | D12777 |
| Chemical and physical data | |
| Formula | C22H30N4O7S |
| Molar mass | 494.56 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
//////Olgotrelvir, STI-1558, HY-156655, CS-0887294, STI 1558, HY 156655, CS 0887294, ZP3BDH359D
Acoltremon
Acoltremon
CAS 68489-09-8
WeightAverage: 289.419
Monoisotopic: 289.204179113
Chemical FormulaC18H27NO2
FDA 2025, 5/28/2025, To treat the signs and symptoms of dry eye disease
Tryptyr |
WS 12
(1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide
Fema No. 4681
N-(4-methoxyphenyl)-p-menthanecarboxamide
- OriginatorInstituto de Neurociencias de Alicante
- DeveloperAlcon; AVX Pharma
- ClassCyclohexanes; Ethers; Eye disorder therapies; Small molecules
- Mechanism of ActionTRPM8 protein stimulants
- RegisteredDry eyes
- 30 May 2025Alcon plans to launch Acoltremon for Dry eyes in USA in the third quarter of 2025
- 28 May 2025Registered for Dry eyes in USA (Ophthalmic) – First global approval
- 05 May 2025FDA assigns PDUFA action date of 30/05/2025 for Acoltremon for Dry eyes
Acoltremon sold under the brand name Tryptyr, is a medication used for the treatment of dry eye syndrome.[1]
PATENT
US 217370
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023114986&_fid=RU437402572
https://patentscope.wipo.int/search/en/detail.jsf?docId=US193167995&_cid=P11-MCE7BB-27500-1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012032209&_fid=US193167995
Medical uses
Acoltremon was approved for medical use in the United States in May 2025, for the treatment of signs and symptoms associated with dry eye disease.[2]
Pharmacology
Acoltremon acts as a potent and selective activator (opener) of the TRPM8 calcium channel, which is responsible for the sensation of coldness produced by menthol.[3] It is slightly less potent as a TRPM8 activator compared to icilin, but is a much more selective TRPM8 ligand when compared to menthol.[4]
Society and culture
Legal status
Acoltremon was approved for medical use in the United States in May 2025.[5]
References
- ^ Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217370s000lbl.pdf
- ^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 29 May 2025. Archived from the original on 3 March 2025. Retrieved 29 May 2025.
- ^ Ma S, Gisselmann G, Vogt-Eisele AK, Doerner JF, Hatt H (October 2008). “Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels”. Pakistan Journal of Pharmaceutical Sciences. 21 (4): 370–378. PMID 18930858.
- ^ Kühn FJ, Kühn C, Lückhoff A (February 2009). “Inhibition of TRPM8 by icilin distinct from desensitization induced by menthol and menthol derivatives”. The Journal of Biological Chemistry. 284 (7): 4102–4111. doi:10.1074/jbc.M806651200. PMID 19095656.
- ^ “Alcon Announces FDA Approval of Tryptyr (acoltremon ophthalmic solution) 0.003% for the Treatment of the Signs and Symptoms of Dry Eye Disease” (Press release). Alcon. 28 May 2025. Archived from the original on 29 May 2025. Retrieved 29 May 2025 – via Business Wire.
External links
- Clinical trial number NCT05285644 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-2)” at ClinicalTrials.gov
- Clinical trial number NCT05360966 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-3)” at ClinicalTrials.gov
| molecular structure | |
| 3D representation | |
| Clinical data | |
|---|---|
| Trade names | Tryptyr |
| Other names | AVX-012, WS-12 |
| License data | US DailyMed: Acoltremon |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 68489-09-8 |
| PubChem CID | 11266244 |
| DrugBank | DB19202 |
| ChemSpider | 9441255 |
| UNII | 1L7BVT4Z4Z |
| KEGG | D13125 |
| ChEMBL | ChEMBL2441929 |
| CompTox Dashboard (EPA) | DTXSID10460636 |
| Chemical and physical data | |
| Formula | C18H27NO2 |
| Molar mass | 289.419 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Beck B, et al. Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators. Cell Calcium. 2007 Mar;41(3):285-94. [Content Brief][2]. Ma S, et al. Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci. 2008 Oct;21(4):370-8. [Content Brief]
///////Acoltremon, FDA 2025, APPROVALS 2025, WS-12, WS 12, Fema No. 4681, Tryptyr, 1L7BVT4Z4Z, AR-15512
NERIGLIATIN
PF 04937319, NERIGLIATIN
N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide
MW 432.43, MF C22 H20 N6 O4
CAS 1245603-92-2
2-Pyrimidinecarboxamide, N,N-dimethyl-5-[[2-methyl-6-[[(5-methyl-2-pyrazinyl)amino]carbonyl]-4-benzofuranyl]oxy]-
N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide
- N,N-Dimethyl-5-({2-Methyl-6-[(5-Methylpyrazin-2-Yl)carbamoyl]-1-Benzofuran-4-Yl}oxy)pyrimidine-2-Carboxamide
- 2-Pyrimidinecarboxamide, N,N-dimethyl-5-[[2-methyl-6-[[(5-methyl-2-pyrazinyl)amino]carbonyl]-4-benzofuranyl]oxy]-
- 7E99B9ZM19
Pfizer Inc. clinical candidate currently in Phase 2 development.
SCHEME
REF
MedChemComm (2011), 2(9), 828-839 81%
WO2010103437
CLINICAL TRIALS
A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)
Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)
Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)
SYNTHESIS
Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.
Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type Il diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM. As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.
It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.
Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.
Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus
Jeffrey A. Pfefferkorn,*a et al
*Corresponding authors
aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421
Med. Chem. Commun., 2011,2, 828-839
DOI: 10.1039/C1MD00116G
http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract
http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf
Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.
N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28). To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethoxyethane (315 mL) in a 3-neck flask equipped with overhead stirring and a condenser at 0 o C was added Me2AlCl (1 M solution in hexanes) (715 mL). The mixture was warmed to room temperature and stirred for 1.5 h. In a separate flask, 26 (52.6 g, 142.5 mmol) was dissolved in dimethoxyethane (210 mL). This mixture was then added to the amine mixture. A gum precipitated and upon scratching the flask it dissipated into a solid. The reaction was refluxed for 3.5 h. Aq. Rochelle’s salt (5 L) and 2-MeTHF (2 L) was added to the mixture and this was allowed to stir with overhead stirring for 14 h, after which time, a yellow solid precipitated. The solid was collected by filtration, washing with 2-MeTHF. The resulting solid was dried in a vacuum oven overnight to afford the desired material (50.0g) in 81% yield.
1 H NMR (400MHz, CDCl3) δ 9.54 (d, J = 1.56 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.14 (d, J = 0.78 Hz, 1H), 7.88 – 7.92 (m, 1H), 7.52 (d, J = 1.37 Hz, 1H), 6.28 (t, J = 0.98 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.55 (s, 3H), 2.49 (d, J = 1.17 Hz, 3H);
MS(ES+ ): m/z 433.4 (M+1), MS(ES- ): m/z 431.3 (M-1).
PAPER
http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract
PAPER
Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578
http://www.sciencedirect.com/science/article/pii/S0960894X13007452
Figure 1.
Glucokinase activators 1 and 2.
PATENT
WO 2010103437
https://www.google.co.in/patents/WO2010103437A1?cl=en
Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).
Preparations of Starting Materials and Key Intermediates
Preparation of Intermediate (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but- 3-enoic acid (I- 1a):
(Ma) To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 ml_, 2650 mmol) and diethyl succinate (840 ml_, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2 x 1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2 x 1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (J1 Ia: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. 1H NMR (CDCI3, 300 MHz) δ ppm 7.48 (s, 1 H), 6.57 (d, 1 H), 6.09 (d, 1 H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).
Preparation of Intermediate ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (1-1 b):
(M b) To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5- methylfuran-2-yl)but-3-enoic acid (1-1 a: 326.6 g, 1 .371 mol) in acetic anhydride (1 .77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1 .5 L) and filtered, washing the solids with dichloromethane (3 x 500 ml_). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2 x 1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (H b: 549.03 g, quantitative). 1H NMR (CDCI3, 300 MHz) δ ppm 8.00-7.99 (m, 1 H), 7.64 (d, 1 H), 6.32-6.32 (m, 1 H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1 .39 (t, 3H).
Preparation of Intermediate ethyl 4-hydroxy-2-methylbenzofuran-6- carboxylate (1- 1 c):
(He) To a stirred solution of ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (Hb: 549.03 g, 1 .37 mol) in ethanol (4.00 L) at room temperature was added potassium carbonate (266 g, 1 .92 mol) in one portion. The reaction mixture was then heated at 600C for 3 hours. Potassium carbonate (100 g, 0.720 mol) was then added in one portion and the reaction mixture was heated at 600C for a further 3 hours. After cooling to room temperature the mixture was diluted with dichloromethane (2 L) and the suspension filtered, washing the solids with dichloromethane (2 x 1 L) (all batches were combined at this point). The combined filtrate and washings were then washed with citric acid (2.5 L of a 1 M aqueous solution), then concentrated in vacuo and the resulting residue purified by dry flash chromatography (hexane then 2:1 hexane:ethyl acetate). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solids were then stirred with hot toluene and decolourising charcoal for 1 hour, followed by filtration of the hot mixture through a pad of celite. The filtrate was allowed to cool and the resulting precipitate isolated by filtration to give desired ethyl 4-hydroxy-2- methylbenzofuran-6-carboxylate (1-1 c: 360 g, 90%) as orange powder.
1H NMR (CDCI3, 300 MHz) δ ppm 7.73-7.73 (m, 1 H), 7.45 (d, 1 H), 6.51 -6.50 (m, 1 H), 5.85 (s, 1 H), 4.39 (q, 2H), 2.48 (d, 3H), 1.40 (t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (96.39 % purity).
Preparation of SM-25-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-
£1:
(SM-2) Oxalyl chloride (47.4g, 369mmol) was added to a suspension of 5-
Bromo-pyrimidine-2-carboxylic acid (5Og, 250mmol) in dichloromethane (821 ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture. The acid dissolved after 30 minutess. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 100%). The 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 250mmol) was dissolved in tetrahydrofuran (828ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373ml, 745mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500ml) and washed with H2O (500ml). The water layer was further extracted with CH2CI2 (5x500ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-/-butylether (650ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100ml) the solid was dried in a vacuum oven at 550C for 12 hourrs to afford the title compound 5-bromo-N,N-dimethylpyhmidine-2-carboxamide (SM-2: 44g, 77%) as a pink solid.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.94 (s, 3 H) 3.13 (s, 3 H) 8.85 (s, 2 H) m/z (M+1 ) = 232.
Preparation of Intermediate Ethyl 4-(2-(dimethylcarbamoyl)Dyrimidin-5- yloxy)-2-methylbenzofuran-6-carboxylate (l-2a):
A mixture of Cs2CO3 (62.1 g, 191 mmol), 5-bromo-N,N- dimethylpyrimidine-2-carboxamide (SM-2: 24g, 104mmol) and ethyl 4- hydroxy-2-methylbenzofuran-6-carboxylate (1-1 c: 2Og, 91 mmol); 1 ,10- phenanthroline (1.64g, 9.07mmol) and copper iodide (864mg, 4.54mmol) in dimethylformamide (200ml) was purged with N2 gas and then heated to 90°C using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 350C and diluted with ethyl acetate (300ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500ml) and ethyl acetate (500ml); however, no separation was observed. Concentrated HCL (20ml) was added to the mixture. When the aqueous phase was about pH1 , the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2x500ml). All organics were combined and back extracted with water (200ml) and brine (500ml). The organics were separated and treated with activated charcoal (10g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 ml_). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 ml_). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 ml_). The solid was dried in the vacuum oven at 550C for 12 hours to afford ethyl 4-(2- (dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (J1 2a) as a yellow solid (18.2g, 54%)
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.12 Hz, 3 H) 2.50 (d, J=0.98 Hz, 3 H) 3.00 (s, 3 H) 3.17 (s, 3 H) 4.41 (d, J=7.22 Hz, 2 H) 6.29 (s, 1 H) 7.62 (d, J=1.17 Hz, 1 H) 8.06 (s, 1 H) 8.50 (s, 2 H). m/z (M+1 ) = 370.5
Preparation of Starting material 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3):
(SM-3) Oxalyl chloride (1 .45g, 1 1 .1 mmol) was added to a suspension of 5-
Bromo-pyrimidine-2-carboxylic acid (1 .5g, 7.4mmol) in dichloromethane (50ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture and all of the acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (1 -6g). 5-Bromo-pyrinnidine-2-carbonyl chloride (1600mg, 7.225mnnol) was dissolved in dichloromethane (25ml) and triethylamine (4.03ml, 28.9mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50ml) and washed with water (50ml) followed by 10% citric acid (50ml) and brine (50ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3): (1.4g, 79.4%) as a brown oil.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 – 1.31 (m, 3 H) 2.99 (d, J=79.05 Hz, 3 H) 3.19 (q, J=7.22 Hz, 1 H) 3.59 (q, J=7.22 Hz, 1 H) 8.84 (d, J=3.12 Hz, 2 H)
Example 2
Preparation of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2- yl)carbamoyl)-benzofuran-4-yloxy)Dyrimidine-2-carboxamide (2):
(2)
To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 ml_) in a 3-neck flask equipped with overhead stirring and a condensor at O0C was added Me2AICI (1 M solution in hexanes) (715 ml_). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2- methylbenzofuran-6-carboxylate (l-2a: 52.6g, 142.5mmol) was dissolved in dimethylether (210 ml_). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2- methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5- methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyhmidine-2-carboxamide (2): (49.98g, 81 %)
1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.49 (d, J=1 .17 Hz, 3H) 2.55 (s, 3H) 2.98 (s, 3 H) 3.14 (s, 3 H) 6.28 (t, J=0.98 Hz, 1 H) 7.52 (d, J=1 .37 Hz, 1 H) 7.88 – 7.92 (m, 1 H) 8.14 (d, J=0.78 Hz, 1 H) 8.37 (s, 1 H) 8.50 (s, 2 H) 9.54 (d, J=1 .56 Hz, 1 H).
m/z (M+1 ) = 433.4, m/z (M-1 )= 431 .5
REFERENCES
Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P
Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751
Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)
OTHERS
///////////Pfizer , PF 04937319, glucokinase activators, Type 2 diabetes, NERIGLIATIN, 7E99B9ZM19
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Nerandomilast
Nerandomilast
CAS 1423719-30-5
C20H25ClN6O2S
| Molecular Weight | 448.97 |
|---|---|
| Formula | C20H25ClN6O2S |
fda 2025, approvals 2025, Jascayd,10/7/2025, To treat idiopathic pulmonary fibrosis
[1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol
Cyclobutanemethanol, 1-[[(5R)-2-[4-(5-chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]-
1-[[(5R)-2-[4-(5-Chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutanemethanol
Nerandomilast (BI 1015550) is an investigational oral medication being studied for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). It is a preferential inhibitor of phosphodiesterase 4B (PDE4B) and has shown potential in slowing lung function decline in patients with IPF.
Key points about nerandomilast:
- Mechanism of Action:Nerandomilast inhibits PDE4B, an enzyme that plays a role in inflammation and fibrosis.
- Clinical Trials:Phase 3 clinical trials have shown that nerandomilast can slow lung function decline in patients with IPF and PPF.
- Efficacy:The trials demonstrated that nerandomilast led to a smaller decline in forced vital capacity (FVC), a measure of lung function, compared to placebo.
- Safety:Diarrhea was the most frequent adverse event, but serious adverse events were balanced across treatment groups.
- Progressive Fibrosing ILDs:Nerandomilast is also being investigated in other progressive fibrosing interstitial lung diseases (ILDs) beyond IPF.
- FDA Designation:Nerandomilast received Breakthrough Therapy Designation from the FDA for the treatment of IPF.
- Not a Cure:While nerandomilast can slow disease progression, it does not cure pulmonary fibrosis.
- Not Yet Approved:Nerandomilast is still an investigational drug and is not yet approved for use.
Nerandomilast (BI 1015550) is an orally active inhibitor of PDE4B with an IC50 value of 7.2 nM. Nerandomilast has good safety and potential applications in inflammation, allergic diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
SCHEME
1H NMR (400 MHz, DMSO-D6) 1.57–1.84 (m, 2H), 1.96 (br d, J = 12.5 Hz, 2H), 2.10–2.21 (m, 2H), 2.24–
2.41 (m, 2H), 2.82–2.98 (m, 2H), 3.06 (br t, J = 11.7 Hz, 2H), 3.13–3.27 (m, 2H), 3.36–3.47 (m, 1H), 3.71 (d, J =
5.64 Hz, 2H), 4.70 (br d, J = 12.5 Hz, 2H), 4.84 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 8.85 (s, 2H).
1H NMR (DMSO-d6, 400 MHz) 1.87–1.92 (m, 2H), 2.12–2.17 (m, 2H), 3.08 (ddd, J = 12.8, 12.8, 2.8 Hz,
2H), 3.21 (m, 1H), 3.34–3.42 (m, 2H), 8.47 (br, 2H), 8.19 (s, 2H).
PATENT
US20150045376
WO2013026797
PAPER
https://pubs.acs.org/doi/10.1021/acs.oprd.4c00309
A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective SNAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).
- [1]. Pouzet P A, et al. Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma. United States. US9150586.[2]. Herrmann FE, et al. BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022 Apr 20;13:838449. [Content Brief]
//////////Nerandomilast, BI 1015550, I5DGT51IB8, fda 2025, approvals 2025, Jascayd,
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
