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Beroterkib
Beroterkib
CAS 2095719-92-7
MF C29H31ClFN5O5 MW584.0 g/mol
(2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1,3-dihydro-2H-1-oxoisoindol-2-yl) -N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide
(2R)-2-[5-[5-chloro-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxo-1H-isoindol-2-yl]-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide
(2R)-2-[5-[5-chloro-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxo-1H-isoindol-2-yl]-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide
extracellular signal-regulated kinases (ERK) inhibitor, antineoplastic, ASTX029, ASTX 029, 14FDK6ISC9, Beroterkib anhydrous, AT 35029
Beroterkib Anhydrous is the anhydrous form of beroterkib, an orally bioavailable inhibitor of the extracellular signal-regulated kinases (ERK) 1 and 2, with potential antineoplastic activity. Upon administration, beroterkib specifically binds to and inhibits both ERK 1 and 2, thereby preventing the activation of mitogen-activated protein kinase (MAPK)/ERK-mediated signal transduction pathways. This results in the inhibition of ERK-dependent tumor cell proliferation and survival. The MAPK/ERK pathway is often upregulated in a variety of tumor cell types and plays a key role in the proliferation, differentiation and survival of tumor cells.
- Study of ASTX029 in Subjects With Advanced Solid TumorsCTID: NCT03520075Phase: Phase 1/Phase 2Status: CompletedDate: 2025-07-03
- Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative NeoplasmsCTID: NCT06284460Phase: Phase 1/Phase 2Status: WithdrawnDate: 2024-10-24
- A Phase 1 Study to Evaluate the Effect of Food on Pharmacokinetics of ASTX029CTID: NCT04466514Phase: Phase 1Status: CompletedDate: 2024-08-02
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017068412&_cid=P21-MK4TZX-17603-1
Example 685: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide
A stirred solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2- yl)propanoic acid (70 mg, 0.168 mmol), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol, HCl (41 mg, 0.185 mmol) and triethylamine (0.094 ml, 0.672 mmol) in DMF (1 ml) was treated with TBTU (65 mg, 0.202 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 ml), was washed successively with 1M KHSO4 (10 ml), NaHCO3 (10 ml), brine (2x 10 ml) and then water (4x 10 ml), was dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, 12 g column, 0- 5% EtOOH in EtOAc) to give a glass, which was triturated with ether (2 ml) to give a solid. The solid was collected by filtration, washed with ether (2x 1 ml) and dried under vacuum at 50°C overnight to give the titlecompound (64.3 mg, 64.3 %) as a cream solid. 1H NMR (DMSO, 400 MHz) δ 8.56 (1H, d), 8.44 (1H, s), 8.07 ‒ 8.00 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 6.76 ‒ 6.64 (3H, m), 4.99 (1H, q), 4.91 (1H, t), 4.86 ‒ 4.70 (2H, m), 4.60 (1H, d), 4.00 ‒ 3.80 (3H, m), 3.76 (3H, s), 3.60 ‒ 3.47 (2H, m), 3.40 ‒ 3.33 (2H, m), 1.84 (2H, d), 1.59 ‒ 1.39 (5H, m). ). LCMS: [M+H]+ = 584.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US237389744&_cid=P21-MK4U5F-21416-1
Example 685: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide
SYN
PAT
- Conjugates comprising hydroxyalkyl starch and a cytotoxic agent and process for their preparationPublication Number: AU-2011276120-B2Priority Date: 2010-07-09Grant Date: 2013-12-19
- Conjugates comprising hydroxyalkyl starch and a cytotoxic agent and process for their preparationPublication Number: AU-2011276120-A1Priority Date: 2010-07-09
- Combustion modified flexible polyurethane foamPublication Number: GB-2124634-APriority Date: 1982-07-26
- Benzolactam compounds as protein kinase inhibitorsPublication Number: ES-2989326-T3Priority Date: 2015-10-21Grant Date: 2024-11-26
- Protein kinase inhibitor benzolactam compoundsPublication Number: CN-114948963-APriority Date: 2015-10-21
- Benzolactam compounds as protein kinase inhibitorsPublication Number: US-2024368136-A1Priority Date: 2015-10-21
- Protein Kinase Inhibitors Benzolactam CompoundsPublication Number: CN-108617166-BPriority Date: 2015-10-21Grant Date: 2022-05-17
- Benzolactam compounds as protein kinase inhibitorsPublication Number: CN-114948963-BPriority Date: 2015-10-21Grant Date: 2025-05-27
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REF
- Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2Publication Name: Journal of Medicinal ChemistryPublication Date: 2021-10-06PMID: 34387469DOI: 10.1021/acs.jmedchem.1c00905
- ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERKPublication Name: Molecular Cancer TherapeuticsPublication Date: 2021-07-30PMID: 34330842DOI: 10.1158/1535-7163.mct-20-0909
//////////////Beroterkib, extracellular signal-regulated kinases (ERK) inhibitor, antineoplastic, ASTX029, ASTX 029, 14FDK6ISC9, Beroterkib anhydrous, AT 35029
Balinatunfib
Balinatunfib
CAS 2248726-53-4
MF C27H24F2N6O2, 502.5 g/mol
(1R,11R)-5-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one
(7R,14R)-11-[2-(1-Aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
(7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methano[1,3]benzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
tumor necrosis factor (TNF) signaling inhibitor, SAR441566, SAR 441566, PLY98MAN4C
- OriginatorSanofi
- ClassAmines; Anti-inflammatories; Antipsoriatics; Antirheumatics; Azabicyclo compounds; Benzimidazoles; Cyclobutanes; Fluorinated hydrocarbons; Heterocyclic compounds with 4 or more rings; Ketones; Phenyl ethers; Pyrimidines; Small molecules
- Mechanism of ActionTumour necrosis factor alpha inhibitors
- Phase IICrohn’s disease; Psoriasis; Rheumatoid arthritis; Ulcerative colitis
- No development reportedInflammation
- 09 Dec 2025Sanofi plans a phase-I trial (In volunteers) in December 2025 (PO, Tablet), (NCT07272629)
- 29 Oct 2025Sanofi plans a phase II SPECIFI-IBD-LTS trial for Crohn’s Disease or Ulcerative Colitis ( Treatment-experienced) in unknown location (PO, Tablet) in December 2025 (NCT07222189)
- 16 Sep 2025Chemical structure information added.
- You need to be a logged in or subscribed to view this c
Balinatunfib (SAR441566) is an experimental drug which acts as a potent small molecule inhibitor of TNF. Rather than blocking TNF receptors, balinatunfib inactivates TNF directly by stabilising an inactive form of the TNF trimer which fails to bind to its target receptors. It is in early stage clinical trials for rheumatoid arthritis and other chronic autoimmune diseases.[1][2]
SYN
PAT
(WO 2016/050975,
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016050975&_cid=P22-MK3F7M-67505-1
Intermediate 40
(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine
Intermediate 38 (5 g, 11.64 mmol) was suspended in toluene (22 mL) and cooled to 0°C before addition of diphenylphosphoryl azide (3.4 mL, 15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16 mmol). The mixture was allowed to warm up to r.t and stirred for 2 hours and subsequently at 45°C overnight. The reaction mixture was diluted with EtOAc (150 mL) and the organic phase washed with a saturated aqueous solution of ammonium chloride (50 mL) then a saturated solution of aqueous sodium bicarbonate (50 mL), and concentrated in vacuo. The crude residue thus obtained was solubilized in THF (100 mL) and water (10 mL), trimethylphosphine (17.46 mL, 17.46 mmol) was added and the reaction mixture stirred overnight. The mixture was concentrated in vacuo, partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was extracted with 0.2M HCl aq (3 x 200 mL). The combined acid layer was stirred in an ice bath, whilst 10% NaOH solution was added with stirring until pH increased to 10. The stirred was continued for further 15 minutes to complete precipitation. The precipitate was filtered, rinsed with water (20 mL), then dried under suction for 10 minutes before drying under high vacuum overnight to afford 3.92 g (78%) of the title compound as an off white solid. LCMS basic: RT 1.96 min. (ES+) 428/430 (M+H)+
EXAMPLE 11
(7R, 14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
Intermediate 40 (3.7 g, 8.6 mmol), activated molecular sieve 4A powder (1.2 g), potassium carbonate (1.5 equiv., 13 mmol) followed by dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.04 equiv., 0.35 mmol) were poured into the center of the 100 mL Glass Parr reaction vessel. 3 cycles of vacuum (~20 mmHg) followed by Argon were applied to the closed reactor.
Anhydrous dimethyl sulfoxide (35 mL) was added, followed by phenol 5M in DMSO (1.1 equiv., 9.5 mmol). The solution was degassed by 3 vacuum (~20 mmHg) / argon cycles followed by 3 cycles of vacuum / CO resulting in a final CO pressure of 1 bar.
The mixture was stirred and heated overnight at 100 °C under the CO atmosphere . The reaction was cooled to 30°C, the reactor vessel was opened and EtOAc (40 mL) was added. The resulting mixture was filtered on a pad of Celite, evaporated in vacuo to yield a green oil.
The residue thus obtained was taken up in EtOAc (100 mL) and the organic layer was washed with water, K2CO3 (saturated aqueous solution) and brine (saturated aqueous solution). The aqueous layer was then re-extracted with EtOAc (1 x 50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The obtained green solid (3.65 g), was taken up in EtOAc, the insoluble material was filtered and rinsed with Et2O to afford 1.06 g (33.1%) of the title compound as a grey solid.
The filtrate can be purified by flash chromatography to provide additional product if required:
LCMS basic: MH+ m/z = 376, RT 1.90 minutes.
1H NMR (300 MHz, DMSO) δ 9.12 (d, 1 H, J = 6.7 Hz), 8.23 (dd, 1 H, J = 7.0, 2.4 Hz), 7.60 (m, 5 H), 7.20 (dd, 1 H, J = 8.7, 2.1 Hz), 6.29 (d, 1 H, J = 7.1 Hz), 4.87 (dd, 1 H, J = 6.7 Hz, 6.7 Hz), 3.46 (m, 1 H), 2.72 (d, 1 H, J = 13.4 Hz).
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US283322316&_cid=P22-MK3EWF-57090-1
Intermediate 3
(7R,14R)-11-Chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
Intermediate 17
tert-Butyl (1-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate
EXAMPLE 6
(7R,14R)-11-[2-(1-Aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
To a solution of Intermediate 17 (18.0 g, 29.9 mmol) in 1,4-dioxane (25 mL) was added 4M hydrochloric acid in 1,4-dioxane (40 mL). The resulting mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was dissolved in water (500 mL) and washed with EtOAc (2×300 mL). The aqueous layer was basified to pH 9 with 2N aqueous sodium hydroxide solution, which resulted in precipitation of a solid. EtOAc (500 mL) was added and the mixture was stirred until all solids had dissolved. The residue was partitioned, then the aqueous layer was further extracted with EtOAc (500 mL). The combined organic layers were dried over Na 2SO 4 and filtered, then concentrated in vacuo and dried overnight under high vacuum. The foamy residue was suspended in a mixture of diethyl ether and hexane (150 mL), then stirred and shaken vigorously, before being concentrated in vacuo, to afford the title compound (12.4 g, 83%) as a white amorphous solid. δ H (400 MHz, DMSO-d 6) 9.05 (s, 2H), 8.32-8.22 (m, 1H), 7.91-7.66 (m, 3H), 7.62 (dd, J8.5, 1.8 Hz, 1H), 7.53-7.46 (m, 2H), 6.31 (d, J7.1 Hz, 1H), 5.26 (d, J 7.2 Hz, 1H), 3.52 (dt, J 14.2, 7.3 Hz, 1H), 3.36 (s, 3H), 2.84 (d, J 13.8 Hz, 1H), 2.63 (dtd, J11.5, 5.6, 2.5 Hz, 2H), 2.38 (s, 2H), 2.16-2.05 (m, 2H), 2.04-1.91 (m, 1H), 1.87-1.73 (m, 1H). LCMS (ES+APCI) [M-NH 2] − 486.0, RT 1.66 minutes (Method 2). LCMS (ES+) [M+H] + 503.0, RT 1.71 minutes (Method 1).
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025008402&_cid=P22-MK3EWF-57090-1
(7R,14R)-1 l-[2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difhroromethoxy)-6-methyl-6,7-dihydro-7, 14-methanobenzimidazo[l,2-b][2,5]benzodiazocin-5(14H)-one.
PAT
- Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2021252012-A1Priority Date: 2017-04-25
- Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: KR-102565132-B1Priority Date: 2017-04-25Grant Date: 2023-08-08
- Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2025127795-A1Priority Date: 2017-04-25
- Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: CN-110582495-BPriority Date: 2017-04-25Grant Date: 2022-04-01
- Fused Pentacyclic Imidazole DerivativesPublication Number: US-2017305932-A1Priority Date: 2014-10-03
- Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: CN-110582495-APriority Date: 2017-04-25
- Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2023250105-A1Priority Date: 2017-04-25
- Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: US-10980814-B2Priority Date: 2017-04-25Grant Date: 2021-04-20
- Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: EP-3939980-A1Priority Date: 2017-04-25
- Process for preparing fused pentacyclic imidazole derivatives and uses thereof as modulators of tnf activityPublication Number: EP-3939980-B1Priority Date: 2017-04-25Grant Date: 2023-07-26
- Preparation of bridged pentacyclic imidazole derivatives as modulators of tnf activity, intermeditates and their preparationPublication Number: WO-2025068505-A1Priority Date: 2023-09-29
- DERIVATIVES OF COMBINED PENTACYCLIC IMIDAZOLES AS MODULATORS OF TNF ACTIVITYPublication Number: HR-P20211927-T1Priority Date: 2017-04-25
- Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: CA-3058980-A1Priority Date: 2017-04-25
- Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: EP-3615534-B1Priority Date: 2017-04-25Grant Date: 2021-09-15
- Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2020046723-A1Priority Date: 2017-04-25
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References
- Vugler A, O’Connell J, Nguyen MA, Weitz D, Leeuw T, Hickford E, et al. (2022). “An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis”. Frontiers in Pharmacology. 13 1037983. doi:10.3389/fphar.2022.1037983. PMC 9709720. PMID 36467083.
- Li Y, Ye R, Dai H, Lin J, Cheng Y, Zhou Y, et al. (January 2025). “Exploring TNFR1: from discovery to targeted therapy development”. Journal of Translational Medicine. 23 (1): 71. doi:10.1186/s12967-025-06122-0. PMC 11734553. PMID 39815286.
| Identifiers | |
|---|---|
| IUPAC name | |
| CAS Number | 2248726-53-4 |
| PubChem CID | 132042903 |
| IUPHAR/BPS | 13583 |
| ChemSpider | 129738176 |
| Chemical and physical data | |
| Formula | C27H24F2N6O2 |
| Molar mass | 502.526 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////////Balinatunfib, tumor necrosis factor (TNF) signaling inhibitor, SAR441566, SAR 441566, PLY98MAN4C
Atirmociclib
Atirmociclib
CAS 2380321-51-5
MF C22H27ClFN5O3,
463.9 g/mol
(3S,4R)-4-[[5-chloro-4-[7-fluoro-2-(2-hydroxypropan-2-yl)-3-propan-2-ylbenzimidazol-5-yl]pyrimidin-2-yl]amino]oxan-3-ol
(3S,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan2-yl)-1H-1,3-benzimidazol-6-yl]pyrimidin-2-yl}amino)oxan-3-ol
1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxpropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol
D-threo-Pentitol, 1,5-anhydro-3-[[5-chloro-4-[4-fluoro-2-(1-hydroxy-1-methylethyl)-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinyl]amino]-2,3-dideoxy-
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6
Atirmociclib is an orally bioavailable inhibitor of cyclin-dependent kinase 4 (CDK4), with potential antineoplastic activity. Upon administration, atirmociclib selectively inhibits CDK4, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1-S-phase transition and leads to cell cycle arrest. This suppresses DNA replication and inhibits tumor cell proliferation. CDK4, a serine/threonine kinase, is upregulated in many tumor cell types and plays a key role in the regulation of both cell cycle progression from the G1-phase into the S-phase and tumor cell proliferation.
Atirmociclib (development code PF-07220060) is an investigational orally bioavailable and CDK4-specific inhibitor being developed by Pfizer for the treatment of various solid tumors, particularly hormone receptor-positive, HER2-negative breast cancer.[1][2] The safety and efficacy of atirmociclib have not been established, as it remains in clinical development as of September 2025.[3][4][5]
SYN
https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02137
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0K3I-13424-1
Example A94 (Scheme A-15): Preparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol
Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0KHW-23947-1
PAT
- 2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: KR-102661053-B1Priority Date: 2018-04-26Grant Date: 2024-04-26
- 2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: KR-20230152182-APriority Date: 2018-04-26
- Cyclin dependent kinase inhibitorsPublication Number: US-11220494-B2Priority Date: 2018-04-26Grant Date: 2022-01-11
- CYCLINE-DEPENDENT KINASE INHIBITORSPublication Number: PE-20201202-A1Priority Date: 2018-04-26
- Cyclin dependent kinase inhibitorsPublication Number: US-2022089580-A1Priority Date: 2018-04-26
- 2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: HR-P20250254-T1Priority Date: 2018-04-26
- Cyclin dependent kinase inhibitorsPublication Number: US-12378232-B2Priority Date: 2018-04-26Grant Date: 2025-08-05
- 2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: EP-3784664-B1Priority Date: 2018-04-26Grant Date: 2025-02-19
- 2-Amino-pyridine or 2-amino-pyrimidine derivatives as cyclin-dependent kinase inhibitorsPublication Number: CN-112313219-BPriority Date: 2018-04-26Grant Date: 2024-04-26
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Mechanism of action
Atirmociclib is designed as a CDK4-specific inhibitor, distinguishing it from dual CDK4/6 inhibitors currently approved for cancer treatment.[6] The drug targets cyclin-dependent kinase 4, which plays a role in cell cycle regulation.[1][7][8]
Atirmociclib functions as a selective inhibitor of the CDK4/cyclin D complex, which plays a crucial role in cell cycle regulation.[4] The drug works by targeting the CDK4 kinase, rendering the retinoblastoma (Rb)/E2F transcription system inactive, which ultimately leads to cell cycle arrest in the G1 phase.[4] This mechanism is particularly effective in tumors that have lost Rb cell cycle-suppressive function, a common feature in various solid tumors.[5]
The selective nature of atirmociclib represents a significant advancement over existing dual CDK4/6 inhibitors.[6] By specifically targeting CDK4 while limiting CDK6 inhibition, atirmociclib is designed to maintain antitumor efficacy while potentially reducing dose-limiting hematologic toxicities, particularly neutropenia, which is believed to be primarily driven by CDK6 inhibition.[9]
Clinical development
Atirmociclib is currently being evaluated in clinical trials for the treatment of advanced solid tumors.[1] Clinical studies are ongoing with estimated completion dates extending to 2027–2028, reflecting the early stage of development for this investigational compound.[1]
Preclinical research published in Cancer Cell in March 2025 reported atirmociclib as a next-generation CDK4-selective inhibitor with enhanced anti-tumor activity and reduced predicted toxicity compared to FDA-approved dual CDK4/6 inhibitors, though these findings require validation in clinical studies.[6]
Preclinical studies
Preclinical research has demonstrated that atirmociclib exhibits enhanced anti-tumor activity compared to FDA-approved dual CDK4/6 inhibitors while showing reduced predicted toxicity.[6] Studies have shown that CDK4-selective inhibition can provide improved preclinical anti-tumor efficacy and safety profiles compared to dual CDK4/6 inhibition strategies.[10]
The preclinical development program has explored combination approaches with various therapeutic modalities, including endocrine therapy, CDK2 inhibition, HER2 antibodies, and immune checkpoint inhibitors.[6] These combination strategies are designed to counter resistance mechanisms to CDK4 inhibition and expand the potential therapeutic applications of cell cycle targeting therapy.[6]
Clinical trials
Atirmociclib has entered clinical development as part of Pfizer’s extensive oncology pipeline.[11] The clinical program is evaluating atirmociclib both as a single agent and in combination with other therapeutic approaches, particularly focusing on patients with hormone receptor-positive, HER2-negative breast cancer.[9][12][13][14][15][16][17]
Early clinical studies have included heavily pretreated patient populations, including those who have previously received CDK4/6 inhibitor therapy.[9] This approach allows for the evaluation of atirmociclib’s potential to overcome resistance to existing CDK4/6 inhibitors and provide therapeutic benefit in patients with limited treatment options.[9]
Safety profile and toxicity
One of the key differentiating features of atirmociclib is its potential for improved safety profile compared to existing dual CDK4/6 inhibitors.[6] The selective targeting of CDK4 while limiting CDK6 inhibition is specifically designed to reduce neutropenia, the most common dose-limiting toxicity associated with current CDK4/6 inhibitors.[18]
The rationale for this approach is based on preclinical evidence suggesting that neutropenia is primarily driven by CDK6 inhibition rather than CDK4 inhibition.[18] By selectively targeting CDK4, atirmociclib aims to maintain therapeutic efficacy while potentially allowing for higher or more sustained dosing without the dose-limiting hematologic toxicities that can compromise treatment outcomes with existing agents.[18]
Regulatory status
As of September 2025, atirmociclib remains an investigational drug that has not received approval from the FDA or other regulatory agencies.[5] The compound is part of Pfizer’s oncology development pipeline.[5]
References
- Pfizer (2 February 2025). A Phase 1/2A Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of Pf-07220060 as a Single Agent and as Part of Combination Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
- Shapiro GI (March 2017). “The evolving role of cyclin-dependent kinase inhibitors in cancer management”. Clinical Advances in Hematology & Oncology. 15 (3): 174–177. PMID 28398270.
- “CDK4 inhibitor PF-07220060”. http://www.cancer.gov. 2 February 2011. Retrieved 3 September 2025.
- “Pfizer Pipeline”. Pfizer.
- “Atirmociclib PF-07220060”. Pfizer Oncology Development. Retrieved 3 September 2025.
- Chang J, Lu J, Liu Q, Xiang T, Zhang S, Yi Y, et al. (March 2025). “Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis”. Cancer Cell. 43 (3): 380–397.e7. doi:10.1016/j.ccell.2025.02.009. PMID 40068596.
- Topacio BR, Zatulovskiy E, Cristea S, Xie S, Tambo CS, Rubin SM, et al. (May 2019). “Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein’s C-Terminal Helix”. Molecular Cell. 74 (4): 758–770.e4. doi:10.1016/j.molcel.2019.03.020. PMC 6800134. PMID 30982746.
- Helsten T, Kato S, Schwaederle M, Tomson BN, Buys TP, Elkin SK, et al. (July 2016). “Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics”. Molecular Cancer Therapeutics. 15 (7): 1682–1690. doi:10.1158/1535-7163.MCT-16-0071. PMID 27196769.
- “ESMO 2024 – combos could be the way forward for CDK2”. ApexOnco. 15 September 2024.
- Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, et al. (March 2025). “CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety”. Cancer Cell. 43 (3): 464–481.e14. doi:10.1016/j.ccell.2025.02.006. PMID 40068598.
- “Pfizer Highlights Diverse Oncology Portfolio and Combination Approaches at ESMO 2024”. Pfizer. 2024.
- Pfizer (12 August 2025). A Phase 1/2a Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetic, Pharmacodynamic, and Anti-Tumor Activity of Pf-07248144 in Participants With Advanced or Metastatic Solid Tumors (Report). clinicaltrials.gov.
- Pfizer (2 July 2025). An Interventional Safety and Efficacy Phase 1/2, Open-Label Study to Investigate Tolerability, Pk, and Antitumor Activity of Vepdegestrant (Arv-47/Pf-07850327), an Oral Proteolysis Targeting Chimera, in Combination With Pf-07220060 in Participants Aged 18 Years and Older With Er+/her2- Advanced or Metastatic Breast Cancer (Report). clinicaltrials.gov.
- Pfizer (14 November 2024). A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PF-07220060 in Combination With Pf-07104091 Plus Endocrine Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
- Pfizer (17 June 2025). (FOURLIGHT-3) (Report). clinicaltrials.gov.
- Pfizer (13 March 2025). An Interventional, Open-Label, Randomized, Multicenter Phase 3 Study of PF-07220060 Plus Letrozole Compared to cdk4/6 Inhibitor Plus Letrozole in Participants Over 18 Years of Age With Hormone Receptor (Hr)-Positive, her2-Negative Advanced/Metastatic Breast Cancer Who Have Not Received Any Prior Systemic Anticancer Treatment for Advanced/Metastatic Disease (FOURLIGHT-1) (Report). clinicaltrials.gov.
- Pfizer (15 November 2024). An Interventional, Open-Label, Randomized, Multicenter, Phase 2 Study of Pf-07220060 Plus Letrozole Compared to Letrozole Alone in Postmenopausal Women 18 Years or Older With Hormone Receptor-Positive, her2-Negative Breast Cancer in the Neoadjuvant Setting (Report). clinicaltrials.gov.
- “Pfizer dials down its atirmociclib ambitions”. ApexOnco. 1 May 2025.
| Identifiers | |
|---|---|
| IUPAC name | |
| CAS Number | 2380321-51-5 |
| PubChem CID | 146219790 |
| ChemSpider | 115009592 |
| UNII | S743GOJ5LJ |
| KEGG | D12834 |
| ChEMBL | ChEMBL5187755 |
| Chemical and physical data | |
| Formula | C22H27ClFN5O3 |
| Molar mass | 463.94 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////////Atirmociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6
Asaretoclax
Asaretoclax
CAS 2363074-01-3
MF C47H57F2N7O7S, MW 902.1 g/mol
4-[4-[[2-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[(4-hydroxy-4-methylcyclohexyl)methylamino]-3-nitrophenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263
Asaretoclax is an orally bioavailable inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), with potential pro-apoptotic and antineoplastic activities. Upon oral administration, asaretoclax targets, binds to and inhibits the activity of Bcl-2. This restores apoptotic processes in tumor cells. Bcl-2 is overexpressed in many cancers and plays an important role in the negative regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US309776623&_cid=P21-MJZ42N-73938-1
Example 34
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1l-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
Intermediate 18
Intermediate 18
4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide
Intermediate 18 was prepared following a procedure described in WO2014/165044A1. LC/MS (ESI) m/z 344.1 [M+H] +.
Intermediate 30
Intermediate 30
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic Acid
| Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 30-1) was prepared following the procedure described in Step 1, Route C for Intermediate 28 using Intermediate 24 in place of Intermediate 22. LCMS (ESI) m/z 591.2 [M+H] +. |
Example 34 was prepared following General Procedure A using Intermediate 30 and Intermediate 18. 1H NMR (400 MHz, DMSO-d 6) δ 11.70 (s, 1H), 11.40 (br s, 1H), 8.59-8.49 (m, 2H), 8.04 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.06 (d, J=9.2 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.99 (t, J=56.8 Hz, 1H), 4.25 (s, 1H), 3.33-3.25 (m, 2H), 3.18-3.05 (m, 4H), 2.97 (s, 2H), 2.40-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94 (s, 6H), 1.71-1.59 (m, 5H), 1.58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 1.27-1.20 (m, 2H), 1.18-1.09 (m, 2H), 1.10 (s, 3H), 0.83 (s, 6H); LC/MS (ESI) m/z 902.6 [M+H] +.
SYN
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US384526484&_cid=P21-MJZ3XL-69589-1
PAT
Publication Number: US-2021009543-A1
Priority Date: 2018-01-10
- Benzamide compoundsPublication Number: CN-118084904-APriority Date: 2018-01-10
- Benzamide compoundsPublication Number: EP-4556469-A1Priority Date: 2018-01-10
- Benzamide compounds as bci inhibitors for the treatment of hivPublication Number: EP-3740487-B1Priority Date: 2018-01-10Grant Date: 2025-01-08
- Benzamide compoundsPublication Number: US-11344546-B2Priority Date: 2018-01-10Grant Date: 2022-05-31
- Benzamide compoundsPublication Number: US-11318134-B2Priority Date: 2018-01-10Grant Date: 2022-05-03
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/////////Asaretoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263
Doxecitine
Doxecitine
CAS951-77-9
MF C9H13N3O4
11/3/2025, FDA 2025, To treat thymidine kinase 2 deficiency in patients who start to show symptoms when they are 12 years old or younger
- CYTIDINE, 2′-DEOXY-
- dCYD
- DEOXYCYTIDINE
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one
Doxecitine is a pyrimidine nucleoside used to treat thymidine kinase 2 deficiency.
Doxecitine is a synthetic form of the naturally occurring pyrimidine deoxyribonucleoside deoxycytidine. It is an essential component of the deoxyribonucleotide pool required for DNA synthesis and repair. Doxecitine is currently approved and marketed as a fixed-dose combination therapy with thymidine (KYGEVVI). This combination is the first and only approved treatment for Thymidine Kinase 2 deficiency.5,6
Deoxycytidine is a deoxyribonucleoside, a component of deoxyribonucleic acid. It is similar to the ribonucleoside cytidine, but with one hydroxyl group removed from the C2′ position. Deoxycytidine can be phosphorylated at C5′ of the deoxyribose by deoxycytidine kinase, converting it to deoxycytidine monophosphate (dCMP), a DNA precursor.[1] dCMP can be converted to dUMP and dTMP.
Doxecitine is the international nonproprietary name.[2]
SYN
Graham A. Mock, Douglas H. Lovern, “N.sup.4 -substituted 2′-deoxycytidine compounds, oligonucleotides including N.sup.4 -labeled 2′-deoxycytidines, and a process for making oligonucleotides with N-modified 2′-deoxycytidines.” U.S. Patent US5633364, issued April, 1995.US5633364
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US37089691&_cid=P21-MJXONM-10154-1
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1982003079&_cid=P21-MJXONM-10154-1
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- Chow E, Miller L, Clearman A, Arnold P, Koenig MK, Russo SN: Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency. Mol Genet Metab. 2025 Aug;145(4):109159. doi: 10.1016/j.ymgme.2025.109159. Epub 2025 Jun 3. [Article]
- Mittur A, VanMeter SA, Orujov E, Glidden P: Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults. Clin Ther. 2024 Jul;46(7):576-587. doi: 10.1016/j.clinthera.2024.06.006. Epub 2024 Jul 18. [Article]
- Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M: Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4. [Article]
- FDA Approved Drug Products: KYGEVVI (doxecitine and doxribtimine) powder, for oral solution (November 2025) [Link]
- UCB: New data on investigational therapy for thymidine kinase 2 deficiency presented at Muscular Dystrophy Association (MDA) 2025 Conference [Link]
- PR Newswire: U.S. FDA approves KYGEVVI™ (doxecitine and doxribtimine), the first and only treatment for adults and children living with thymidine kinase 2 deficiency (TK2d) [Link]
| Names | |
|---|---|
| IUPAC name2′-deoxycytidine | |
| Systematic IUPAC name4-Amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2(1H)-one | |
| Other namesdoxecitine | |
| Identifiers | |
| CAS Number | 951-77-9 |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:15698 |
| ChEMBL | ChEMBL66115 |
| ChemSpider | 13117 |
| ECHA InfoCard | 100.012.231 |
| MeSH | Deoxycytidine |
| PubChem CID | 13711 |
| UNII | 0W860991D6 |
| CompTox Dashboard (EPA) | DTXSID70883620 |
| InChI | |
| SMILES | |
| Properties | |
| Chemical formula | C9H13N3O4 |
| Molar mass | 227.217 |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references | |
References
- Staub M, Eriksson S (2006). “The Role of Deoxycytidine Kinase in DNA Synthesis and Nucleoside Analog Activation”. In Peters GJ (ed.). Deoxynucleoside Analogs In Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. pp. 29–52. doi:10.1007/978-1-59745-148-2_2. ISBN 978-1-59745-148-2.
- World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.
- Kim KW, Roh JK, Wee HJ, Kim C (2016). “Molecular Targeted Anticancer Drugs”. In Kim KW, Roh JK, Wee HJ, Kim C (eds.). Cancer Drug Discovery: Science and History. Springer Netherlands. pp. 175–238. doi:10.1007/978-94-024-0844-7_9. ISBN 978-94-024-0844-7.
- Guo M, Zhang L, Du Y, Du W, Liu D, Guo C, et al. (March 2018). “Enrichment and Quantitative Determination of 5-(Hydroxymethyl)-2′-deoxycytidine, 5-(Formyl)-2′-deoxycytidine, and 5-(Carboxyl)-2′-deoxycytidine in Human Urine of Breast Cancer Patients by Magnetic Hyper-Cross-Linked Microporous Polymers Based on Polyionic Liquid”. Analytical Chemistry. 90 (6): 3906–3913. doi:10.1021/acs.analchem.7b04755. PMID 29316399.
- “FDA approves 1st drug for thymidine kinase 2 deficiency”. U.S. Food and Drug Administration. 3 November 2025. Retrieved 4 November 2025.
This article incorporates text from this source, which is in the public domain.
External links
- “Doxecitine ( Code – C420 )”. EVS Explore.
- MeSH 68003841
/////////doxecitine, deoxycytidine, CYTIDINE, 2′-DEOXY-, dCYD, FDA 2025, APPROVALS 2025
Amogammadex
Amogammadex
CAS 1309580-40-2
MF C88H136N8O56S8 MW2458.56
(2R)-2-acetamido-3-[[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)-10,15,20,25,30,35,40-heptakis[[(2R)-2-acetamido-2-carboxyethyl]sulfanylmethyl]-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan-5-yl]methylsulfanyl]propanoic acid
L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-
AMOGAMMADEX [INN]
CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL)
cyclooctakis-(1→4)-{6-S-[(2R)-2-acetamido-2-carboxyethyl]-6-thio-α-Dglucopyranosyl}
rocuronium and vecuronium reversal agent, L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-
AMOGAMMADEX [INN]
CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL)
Pat
WO2012068981
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012068981&_cid=P21-MJW9RG-10499-1
CD-8
Weigh 23.7 g (0.088 mol) of N-acetylcysteine and measure 160 ml of dry DMF. Add both to a dry three-necked flask and stir until completely dissolved. Cool the reaction solution to approximately -10°C in a constant temperature bath. Slowly add 8.81 g of sodium hydride (60%) in portions under argon protection and mechanical stirring, maintaining the temperature below -5°C. After the addition is complete, continue stirring until no more bubbles emerge, then transfer the solution to approximately 5°C and react until no more bubbles emerge (approximately 2-3 hours).
With the temperature controlled at approximately 5°C in an ice bath, add 8.38 g (3.85 mmol) of DMF solution of 6-per-deoxy-6-per-iodo-γ-cyclodextrin to the reaction solution of the fully reacted N-acetylcysteine sodium salt. Under argon protection, mechanically stir to ensure homogeneity and continue stirring for 30 min. Gradually raise the temperature of the reaction solution to 70°C and react for 12 h. Then cool the reaction solution to room temperature, filter, wash the filter cake twice with DMF, and then wash with acetone until triphenylphosphine and triphenyloxyphosphine are removed. Dry under reduced pressure to obtain crude sodium salt. Dissolve the crude sodium salt in glacial acetic acid, and then pass dry hydrogen chloride gas into the solution under ice bath cooling. A white solid precipitates after 20 min. Filter after no more white solid precipitates (approximately 1 h). Dry acetone was gradually added to the filtrate, and a solid precipitated out. The mixture was filtered, and the filter cake was washed with acetone until there was no sour taste. The cake was dried under reduced pressure to obtain 6-per-deoxy-6-per-(N-acetylglycine methyl)thioether-γ-cyclodextrin (CD-8) with a yield of 48%.
Ή NMR spectra of CD-8 in heavy water (D2O ) : 52.02 (CH3,m,3H), 2.69,2.44 (CH2,m,2H), 3.02 (CH,m,H), 3.06,2.81 (CH2,m,2H), 3.73 (2CH,m,2H), 4.19 (CH,m,H), 4.74 (CH,m,H), 5.03 (CH,s,H) ppm.
PAT
CN102060941
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84636898&_cid=P21-MJW9XY-15988-1
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////////amogammadex
Alizulatide vixocianine
Alizulatide vixocianine
CAS 2924859-51-6
MF C115H145N17O25S, 2,197.55
L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt
4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate
diagnostic imaging agent, 8M3Q8XZ6MJ
Alizulatide vixocianine is a polypeptide that can be discovered through polypeptide screening. Polypeptide screening is a research tool mainly based on immunoassay methods to identify active polypeptides. It can be applied to protein interaction, functional analysis, antigenic epitope screening, especially in the fields of active molecule research and development.
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/////////alizulatide vixocianine, diagnostic imaging agent, 8M3Q8XZ6MJ
Aleniglipron
Aleniglipron
CAS 2685823-26-9
MF C49H55FN9O6P MW916.0 g/mol
3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX
Aleniglipron (development code GSBR-1290) is a small-molecule GLP-1 agonist developed by Structure Therapeutics.[1] It is delivered orally and is in a Phase II trial as of 2023.[2][3][4] In June 2024, Structure Therapeutics reported positive topline data from a Phase 2a obesity study in which GSBR-1290 demonstrated clinically meaningful and statistically significant placebo-adjusted mean weight loss and generally favorable safety and tolerability results.[5]
- Aleniglipron Phase 2 Body Composition StudyCTID: NCT07169942Phase: Phase 2Status: Active, not recruitingDate: 2025-10-31
- A Dose-Range Study of Aleniglipron (GSBR-1290) in Participants Living With Obesity or Overweight With at Least One Weight-related ComorbidityCTID: NCT06703021Phase: Phase 2Status: Active, not recruitingDate: 2025-09-15
- A Phase 2b, Dose-range Finding Study of the Efficacy and Safety of Multiple Doses of Aleniglipron (GSBR-1290) in Participants Living With Obesity or Overweight With at Least One Weight-related ComorbidityCTID: NCT06693843Phase: Phase 2Status: Active, not recruitingDate: 2025-08-26
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US367934715&_cid=P10-MJRZ0C-74156-1
Example 2: Synthesis of
3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 121a)
Step A: (4-bromo-2-fluorophenyl)diethylphosphine oxide
| 1H NMR (400 MHz, DMSO-d 6) δ 7.63-7.73 (m, 3H), 1.95-2.08 (m, 2H), 1.80-1.92 (m, 2H), 0.80-1.10 (m, 6H). |
Step B: (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide
| 1H NMR (600 MHz, DMSO-d 6) δ 7.75-7.76 (m, 1H), 7.11 (dd, J=13.2, 8.4 Hz, 1H), 6.63-6.80 (m, 2H), 2.71 (d, J=5.4 Hz, 3H), 1.88-1.94 (m, 4H), 0.90-1.05 (m, 6H). |
Step C: tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate
Step D: (5)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride
Step E: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one
PAT
- Heterocyclic glp-1 agonistsPublication Number: EP-4097099-A1Priority Date: 2020-02-07
- Heterocyclic GLP-1 agonistsPublication Number: CN-115698003-APriority Date: 2020-02-07
- Heterocyclic glp-1 agonistsPublication Number: EP-4097099-B9Priority Date: 2020-02-07Grant Date: 2025-04-30
- Heterocyclic glp-1 agonistsPublication Number: EP-4458834-A2Priority Date: 2020-02-07
- Heterocyclic GLP-1 agonistsPublication Number: US-11926643-B2Priority Date: 2020-02-07Grant Date: 2024-03-12
- Heterocyclic GLP-1 agonistsPublication Number: CN-119823184-APriority Date: 2020-02-07
- Heterocyclic GLP-1 agonistsPublication Number: CN-119841865-APriority Date: 2020-02-07
- Heterocyclic GLP-1 agonistsPublication Number: CN-119874775-APriority Date: 2020-02-07
- Heterocyclic GLP-1 agonistsPublication Number: US-11492365-B2Priority Date: 2020-02-07Grant Date: 2022-11-08
- Heterocyclic GLP-1 agonistsPublication Number: CN-115698003-BPriority Date: 2020-02-07Grant Date: 2024-10-11
- Heterocyclic glp-1 agonistsPublication Number: US-2022213130-A1Priority Date: 2020-02-07
- Heterocyclic glp-1 agonistsPublication Number: EP-4097099-B1Priority Date: 2020-02-07Grant Date: 2024-06-26
- Heterocyclic glp-1 agonistsPublication Number: US-2023174565-A1Priority Date: 2020-02-07
- Salts and solid forms of a compound having glp-1 agonist activityPublication Number: WO-2024125602-A1Priority Date: 2022-12-15
- Salts and solid forms of a compound having glp-1 agonist activityPublication Number: EP-4634180-A1Priority Date: 2022-12-15
- Heterocyclic glp-1 agonistsPublication Number: US-2024366639-A1Priority Date: 2021-08-12
- Heterocyclic glp-1 agonistsPublication Number: WO-2023016546-A1Priority Date: 2021-08-12
- Heterocyclic glp-1 agonistsPublication Number: WO-2021155841-A1Priority Date: 2020-02-07
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References
- Mao, Ting; Meng, Qinghua; Zhang, Haizhen; Zhang, Jinqiang J.; Shi, Songting; Guan, Zhibo; Jiang, Xinglong; Zhang, Fang; Lei, Hui; Lin, Xichen (20 June 2023). “760-P: Discovery of GSBR-1290, a Highly Potent, Orally Available, Novel Small Molecule GLP-1 Receptor Agonist”. Diabetes. 72 (Supplement_1) 760-P. doi:10.2337/db23-760-P. S2CID 259430363.
- “Structure Therapeutics Initiates Phase 2a Study of Oral GLP-1 agonist GSBR-1290 for the Treatment of Type 2 Diabetes and Obesity”. BioSpace. 25 May 2023. Retrieved 4 November 2023.
- “Structure announces positive results from oral GLP-1 receptor agonist gsbr-1290”. Bariatric News. 2 October 2023. Retrieved 4 November 2023.
- Satija, Bhanvi (29 September 2023). “Structure Therapeutics surges as early data from obesity pill tops expectations”. Reuters. Retrieved 4 November 2023.
- “Structure Therapeutics Reports Positive Topline Data from its Phase 2a Obesity Study and Capsule to Tablet PK Study for its Oral Non-Peptide Small Molecule GLP-1 Receptor Agonist GSBR-1290”. BioSpace. 2024-06-03. Retrieved 2024-10-24.
| Legal status | |
|---|---|
| Legal status | Investigational |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2685823-26-9 |
| PubChem CID | 164809721 |
| DrugBank | DB18551 |
| UNII | Z6XCL6R9SX |
| Chemical and physical data | |
| Formula | C49H55FN9O6P |
| Molar mass | 916.008 g·mol−1 |
| InChI | |
//////////Aleniglipron, glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX
Limnetrelvir
Limnetrelvir
CAS 2923500-04-1
MF C27H23F4N5O4 MW 557.50
N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide
N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-
(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamide
antiviral, ABBV-903, ABBV 903, 4TPS988XGG
Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research.
SYN
Example 1 – Synthesis of Compound (2) (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide
Compound 2F – Synthesis of 8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid
[00035] A suspension of 7-fluoroindoline-2,3-dione (55 g, 333 mmol), malonic acid (41.6 g, 400 mmol) and sodium acetate (68.3 g, 833 mmol) in acetic acid (500 mL) was heated at 112 °C overnight. The reaction mixture was cooled to room temperature and poured into cold 0.4 M aqueous HCl (2200 mL). The precipitate was collected by filtration and rinsed thoroughly with ice-cold water (~250 mL) followed by methyl tert-butyl ether (~100 mL) and then concentrated twice from acetonitrile with high vacuum. The materials were largely dissolved into 1 M aqueous NaOH (370 mL) and filtered through diatomaceous earth with a 0.1 M aqueous NaOH (50 mL) rinse. Then the filtrate was washed thrice with dichloromethane (3 x 200 mL) which removed the color. After this aqueous layer was filtered again through diatomaceous earth, it was acidified by the dropwise addition of concentrated aqueous HCl (33 mL, ~0.4 moles). The material was collected by filtration. After prolonged drying under heat and vacuum, the material was treated with water (1 L) and the mixture was made acidic by the addition of a small amount of 1 M aqueous HCl. The suspension was heated to 80 °C and then allowed to slowly cool to room temperature. The resulting material was collected by filtration, washed with 0.01 M aqueous HCl (150 mL) and dried under vacuum at 80 °C to provide the title compound (2F).1H NMR (500 MHz, DMSO-d6) δ ppm 14.00 (bs, 1H), 12.07 (bs, 1H), 8.00 (dd, J = 8.2, 1.2 Hz, 1H), 7.49 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.23 (ddd, J = 8.2, 8.1, 5.2 Hz, 1H), 6.95 (s, 1H); 13C NMR (101 MHz, DMSO-d6, 90 °C) δ ppm 165.75 – 165.73 (m), 160.30, 148.75 (d, J = 246.0 Hz), 140.85 – 140.80 (m), 128.11 (d, J = 13.7 Hz), 123.85, 121.60 – 121.53 (m), 121.53 – 121.43 (m), 117.70 – 117.65 (m), 115.33 (d, J = 17.2 Hz); 19F NMR (376 MHz, DMSO-d6, 90 °C) δ ppm -130.47 (dd, J = 10.9, 5.3 Hz); MS (APCI, M+H+) m/z 208.
Compound 2G – Synthesis of (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (2)
00036] To a mixture of Compound 2F (29.84 g, 144 mmol) in anhydrous N,N-dimethylformamide (360 mL) was added DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride) (43.17 g, 156 mmol) over twelve minutes at room temperature. After the suspension had been stirred forty minutes, it was added over eight minutes to a suspension of Compound 2E (≤120 mmol) and N-methylmorpholine (16 mL, 146 mmol) in N,N-dimethylformamide (120 mL) with a N,N-dimethylformamide (20 mL) rinse. After forty minutes, the reaction mixture was added to rapidly stirred 0.1 M aqueous K2HPO4 (2.5 L) and extracted four times with 4:1 isopropyl acetate / heptanes then once with isopropyl acetate alone. The product, which had begun to precipitate out from the combined extracts, was separated by decantation and filtration, then washed with dichloromethane. The remaining aqueous phase was extracted twice more with isopropyl acetate and all the organic extracts were combined, then washed with additional 0.1 M aqueous K2HPO4 followed by water, dried (Na2SO4), and filtered. The filtrate was concentrated with the dichloromethane wash of the material collected above. The residue was concentrated, dissolved in acetonitrile / CH2Cl2, filtered, and purified by chromatography on silica (20 to 100% acetonitrile / CH2Cl2). The collected fractions were concentrated to a small volume, and stirred in ethyl acetate overnight.
[00037] The suspension was heated at 70 °C for twenty minutes, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether followed by methyl tert-butyl ether before being dried under vacuum with heat. The material obtained previously from the early extracts were also stirred in ethyl acetate, heated at 70 °C, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether rinse followed by methyl tert-butyl ether. The material was dried overnight under vacuum to provide the title compound (2).1H NMR (500 MHz, DMSO-d6) δ ppm 11.96 (s, 1H), 9.03 – 8.84 (m, 1H), 8.21 – 8.18 (m, 1H), 7.98 – 7.93 (m, 1H), 7.56 – 7.50 (m, 1H), 7.49 – 7.43 (m, 1H), 7.21 – 7.15 (m, 1H), 6.66 – 6.59 (m, 1H), 4.51 – 4.40 (m, 1H), 3.73 – 3.55 (m, 6H), 3.54 – 3.22 (m, 6H), 2.29 – 2.18 (m, 1H), 2.07 – 1.95 (m, 1H); 1H NMR (400 MHz, DMSO-d6, 90 °C) δ ppm 11.47 (bs, 1H), 8.77 – 8.47 (m, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.1, 1.2 Hz, 1H), 7.39 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.15 (ddd, J = 8.1, 8.1, 5.1 Hz, 1H), 6.60 (s, 1H), 4.54 – 4.43 (m, 1H), 3.74 – 3.20 (m, 12H), 2.31 – 2.21 (m, 1H), 2.06 – 1.96 (m, 1H); 13C NMR (101 MHz, DMSO-d6, 90 °C) δ
ppm 166.61, 165.97, 161.31, 149.59 (d, J = 246.3 Hz), 148.95, 146.10 – 146.03 (m), 136.00, 135.65, 133.13 (q, J = 6.1 Hz), 128.84 – 128.63 (m), 123.76 (q, J = 273.7 Hz), 122.19, 122.16, 122.12, 121.60, 118.99 – 118.91 (m), 117.75, 116.17 (d, J = 17.3 Hz), 105.57, 66.04, 57.95, 51.06, 50.35, 47.74, 42.35, 31.54; 19F NMR (376 MHz, DMSO-d6) δ ppm -57.54 – -58.10 (m), -130.02 – -130.15 (m); 19F NMR (376 MHz, DMSO-d6, 90 °C) δ ppm -58.37 – -58.97 (m), -130.96 (dd, J = 11.0, 5.1 Hz). MS (APCI, M+H+) m/z 558.
PAT
- Pyrrolidine Main Protease Inhibitors as Antiviral AgentsPublication Number: US-2024158368-A1Priority Date: 2022-10-14
- Pyrrolidine main protease inhibitors as antiviral agentsPublication Number: WO-2024081351-A1Priority Date: 2022-10-14
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/////////limnetrelvir, antiviral, ABBV-903, ABBV 903, 4TPS988XGG
Aficamten
Aficamten
C18H19N5O2, 337.4 g/mol
FDA 2025, APPROVALS 2025, Myqorzo, 12/19/2025, To treat symptomatic obstructive hypertrophic cardiomyopathy
CK-3773274, B1I77MH6K1, BAY-3723113; CK 3773274; CK 274; MYQORZO
N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1-methylpyrazole-4-carboxamide
- (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide
- N-((1R)-5-(5-Ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide
- OriginatorCytokinetics
- DeveloperBayer; Cytokinetics; Sanofi
- ClassAmides; Cardiovascular therapies; Heart failure therapies; Indenes; Oxadiazoles; Pyrazoles; Small molecules
- Mechanism of ActionCardiac myosin inhibitors
- Orphan Drug StatusYes – Hypertrophic cardiomyopathy
- RegisteredHypertrophic cardiomyopathy
- 20 Dec 2025Cytokinetics plans to launch aficamten in the USA in second half of January 2026
- 19 Dec 2025Registered for Hypertrophic cardiomyopathy in USA (PO)
- 19 Dec 2025Aficamten carries a black box warning for the risk of heart failure
Aficamten, sold under the brand name Myqorzo, is a medication used for the treatment of symptomatic obstructive hypertrophic cardiomyopathy.[1] It is a cardiac myosin inhibitor[2] developed by Cytokinetics.[3][4]
Aficamten binds directly to the motor domain of cardiac myosin and prevents it from entering the force-producing state.[5] This lowers cardiac contractility, leading to reduced left ventricular outflow tract obstruction in people with hypertrophic cardiomyopathy.[5]
Aficamten was approved for medical use in the United States in December 2025.[6]
Medical uses
Aficamten is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms.[1][6]
Symptomatic obstructive hypertrophic cardiomyopathy is an inherited condition where people have thickened heart muscle and reduced blood flow from the left side of the heart to the rest of the body, causing symptoms such as shortness of breath, fatigue, and potentially life-threatening cardiac events.[6]
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019144041&_cid=P10-MJP428-30255-1
Example 15
Synthesis of Compound 184
1. Synthesis of Intermediate 15-2:
[0262] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl] carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105 oC for 8 h, cooled to r.t., concentrated under reduced pressure, and purified by silica gel
chromatography (EA/PE, 1/9) to give 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid.
2. Synthesis of Intermediate 15-3:
[0263] To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (17.6 g, 53.4 mmol, 1.0 equiv) in DCM (120 mL) was added TFA (24 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL) and the pH was adjusted to 12 with sodium hydroxide solution (2 N). The mixture was then extracted with dichloromethane (200 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as a brown oil. 3. Synthesis of Compound 184:
[0264] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (6.1 g, 48.4 mmol, 1.0 equiv) in DMF (300 mL) were added DIEA (12.6 g, 97.5 mmol, 2.0 equiv), HOAt (19.8 g, 145.8 mmol, 3.0 equiv), and EDCI (28 g, 146.1 mmol, 3.0 equiv). The mixture was stirred for 15 min, and (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (11.2 g, 48.9 mmol, 1.0 equiv) was then added. The mixture was then stirred for 3 h, diluted with DCM, washed with NH4Cl solution three times, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA/PE, 74/26) to give an intermediate product. The intermediate product was triturated with a mixture of EA and PE (1/10) to afford 14.5 g (88%) of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 184) as a white solid. LRMS (ES) m/z 338 (M+H). 1H-NMR: (DMSO, 300MHz, ppm): į 8.41 (1H, d, J = 8.4 Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J = 7.9 Hz), 5.53 (1H, q, J = 8.3 Hz), 3.84 (3H, s), 3.13-2.81 (4H, m), 2.44 (1H, dd, J = 7.9, 4.7 Hz), 1.95 (1H, m), 1.33 (3H, t, J = 7.5 Hz).
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021011807&_cid=P10-MJP428-30255-1
(R)-N-(5-(5-ethyl- 1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-l-yl)-1-methyl-1H-pyrazole-4-carboxamide,
SYN
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01290
PAT
- Cardiac sarcomere inhibitorsPublication Number: US-10836755-B2Priority Date: 2018-01-19Grant Date: 2020-11-17
- Cardiac sarcomere inhibitorsPublication Number: US-12065436-B2Priority Date: 2018-01-19Grant Date: 2024-08-20
- Cardiac sarcomere inhibitorsPublication Number: US-2023119665-A1Priority Date: 2018-01-19
- Cardiac sarcomere inhibitorsPublication Number: US-11472796-B2Priority Date: 2018-01-19Grant Date: 2022-10-18
- Cardiac sarcomere inhibitorsPublication Number: US-2025059173-A1Priority Date: 2018-01-19
- Dihydrobenzofuran and indene analogs as myocardial inhibitorsPublication Number: CN-117964573-APriority Date: 2018-01-19
- Cardiac sarcomere inhibitorsPublication Number: TW-202436291-APriority Date: 2018-01-19
- Dihydrobenzofurans and indene analogs as cardiomyome inhibitorsPublication Number: CN-111757875-BPriority Date: 2018-01-19Grant Date: 2024-01-09
- Dihydrobenzofuran and indene analogs as myocardial inhibitorsPublication Number: CN-117924208-APriority Date: 2018-01-19
- Dihydrobenzofuran and indene analogs as inotropic agentsPublication Number: CN-111757875-APriority Date: 2018-01-19
- Cardiac sarcomere inhibitorsPublication Number: TW-I835770-BPriority Date: 2018-01-19Grant Date: 2024-03-21
- Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitorsPublication Number: EP-3740481-A1Priority Date: 2018-01-19
- Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitorsPublication Number: EP-3740481-B9Priority Date: 2018-01-19Grant Date: 2024-10-23
- Cardiac sarcomere inhibitorsPublication Number: US-2021147399-A1Priority Date: 2018-01-19
- Cardiac sarcomere inhibitorsPublication Number: EP-4491622-A2Priority Date: 2018-01-19
REF
- Clinical Evaluation of the Effect of Aficamten on <scp>QT</scp>/<scp>QTc</scp> Interval in Healthy ParticipantsPublication Name: Clinical and Translational SciencePublication Date: 2025-04PMCID: PMC11979292PMID: 40200648DOI: 10.1111/cts.70218
- Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of AficamtenPublication Name: Clinical PharmacokineticsPublication Date: 2025-02-05PMCID: PMC11954688PMID: 39907965DOI: 10.1007/s40262-025-01481-9
- The clinical utility of cardiac myosin inhibitors for the management of hypertrophic cardiomyopathy: a scoping reviewPublication Name: Heart Failure ReviewsPublication Date: 2024-12-17PMCID: PMC11802616PMID: 39690360DOI: 10.1007/s10741-024-10476-w
- Obstructive Hypertrophic Cardiomyopathy: A Review of New TherapiesPublication Name: Future CardiologyPublication Date: 2023-10PMID: 37933625DOI: 10.2217/fca-2023-0056
- Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic CardiomyopathyPublication Name: American journal of cardiovascular drugs : drugs, devices, and other interventionsPublication Date: 2023-08-01PMID: 37526885DOI: 10.1007/s40256-023-00599-0
- Synthesis of AficamtenPublication Name: SynfactsPublication Date: 2021-11-17DOI: 10.1055/s-0041-1737088
- Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic CardiomyopathyPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-10-04PMID: 34606259DOI: 10.1021/acs.jmedchem.1c01290
- Emerging Medical Treatment for Hypertrophic CardiomyopathyPublication Name: Journal of Clinical MedicinePublication Date: 2021-03-01PMCID: PMC7957690PMID: 33804412DOI: 10.3390/jcm10050951
- Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle DiseasesPublication Name: International Journal of Molecular SciencesPublication Date: 2020-12-16PMCID: PMC7767104PMID: 33339418DOI: 10.3390/ijms21249599
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Contraindiations
Use with rifampin is contraindicated.[1]
Adverse effects
The US prescription label for aficamten contains a boxed warning that it reduces left ventricular ejection fraction and can cause heart failure due to systolic dysfunction.[1]
History
The effectiveness and safety of aficamten were studied in 282 adults with symptomatic obstructive hypertrophic cardiomyopathy randomly assigned to receive aficamten or placebo for 24 weeks.[6] At the end of the study, participants receiving aficamten had an increase in exercise capacity measured by peak oxygen uptake compared to no change in exercise capacity among those receiving placebo.[6] Also, 59 percent of participants receiving aficamten experienced an improvement in physical activity limitations (measured using the New York Heart Association Classification system) compared to 24 percent of individuals receiving placebo.[6]
Society and culture
Legal status
Aficamten was approved for medical use in the United States in December 2025.[6][7] The US Food and Drug Administration granted the application for aficamten orphan drug and breakthrough therapy designations.[6]
In December 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Myqorzo, intended for the treatment of adults with obstructive hypertrophic cardiomyopathy.[5] The applicant for this medicinal product is Cytokinetics (Ireland) Limited.[5]
Names
Aficamten is the international nonproprietary name.[8]
Aficamten is sold under the brand name Myqorzo.[6]
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219083s000lbl.pdf [bare URL PDF]
- Chuang, Chihyuan; Collibee, Scott; Ashcraft, Luke; Wang, Wenyue; Vander Wal, Mark; Wang, Xiaolin; et al. (October 2021). “Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy”. Journal of Medicinal Chemistry. 64 (19): 14142–14152. doi:10.1021/acs.jmedchem.1c01290. ISSN 0022-2623. PMID 34606259. S2CID 238355647.
- Zhao, Xue; Liu, Hongzhong; Tian, Wei; Fang, Ligang; Yu, Mengyang; Wu, Xiaofei; et al. (2023). “Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study”. Frontiers in Pharmacology. 14 1227470. doi:10.3389/fphar.2023.1227470. PMC 10482267. PMID 37680714.
- Sebastian, Sneha Annie; Padda, Inderbir; Lehr, Eric J.; Johal, Gurpreet (September 2023). “Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy”. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions. 23 (5): 519–532. doi:10.1007/s40256-023-00599-0. ISSN 1179-187X. PMID 37526885. S2CID 260348901.
- “Myqorzo EPAR”. European Medicines Agency (EMA). 12 December 2025. Retrieved 22 December 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “FDA approves drug to improve functional capacity and symptoms in adults with rare inherited heart condition”. U.S. Food and Drug Administration (FDA) (Press release). 22 December 2025. Retrieved 22 December 2025. This article incorporates text from this source, which is in the public domain.
- “Cytokinetics Announces FDA Approval of Myqorzo (aficamten) for the Treatment of Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy to Improve Functional Capacity and Symptoms” (Press release). Cytokinetics. 19 December 2025. Retrieved 22 December 2025 – via GlobeNewswire News Room.
- World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
Further reading
- Maron, Martin S.; Masri, Ahmad; Choudhury, Lubna; Olivotto, Iacopo; Saberi, Sara; Wang, Andrew; et al. (January 2023). “Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy”. Journal of the American College of Cardiology. 81 (1): 34–45. doi:10.1016/j.jacc.2022.10.020. hdl:2158/1295661. PMID 36599608. S2CID 255472935.
External links
- Clinical trial number NCT05186818 for “Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (SEQUOIA-HCM) (SEQUOIA-HCM)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Myqorzo |
| Other names | CK-3773274 |
| License data | US DailyMed: Aficamten |
| Routes of administration | By mouth |
| Drug class | Cardiac myosin inhibitor |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2364554-48-1 |
| PubChem CID | 139331495 |
| DrugBank | DB18490 |
| ChemSpider | 114935503 |
| UNII | B1I77MH6K1 |
| KEGG | D12253 |
| ChEMBL | ChEMBL4847050 |
| PDB ligand | 6I6 (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C18H19N5O2 |
| Molar mass | 337.383 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////////Aficamten, FDA 2025, APPROVALS 2025, Myqorzo, CK-3773274, CK 3773274, B1I77MH6K1, BAY 3723113; CK 3773274; CK 274, MYQORZO
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
