Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.
E Scott PriestleyJacques BanvilleDaniel DeonLaurence DubéMarc GagnonJulia GuyPhilippe LapointeJean-François LavalléeAlain MartelSerge PlamondonRoger RémillardEdward RuedigerFrançois TremblayShana L PosyVictor R GuarinoJeremy M RichterJianqing LiAnuradha GuptaVetrichelvan MuthalaguT J BalapragalathanArvind MathurJi HuaMario CallejoJocelyne GuayChi Shing SumMary Ellen CvijicCarol WatsonPancras WongJing YangMichel BouvierDavid A GordonRuth R WexlerAnne MarinierPublished in: Journal of medicinal chemistry (2022)
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.