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Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Jul 14; Vol. 65 (13), pp. 8843-8854. Date of Electronic Publication: 2022 Jun 21. - Publication Year :
- 2022
-
Abstract
- Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 ( 43 ), and a backup clinical candidate, BMS-986141 ( 49 ). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35729784
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c00359