Discovery of (E)‐5,5‐Difluoro‐1‐[2‐[5‐(3‐fluorophenyl)pyridin‐2‐yl]vinyl]octahydrospiro(indene‐2,5′‐oxazolidin)‐2′‐one as a PAR1 Antagonist.

In a previous study, we showed that several octahydroindene derivatives are potent protease activated receptor 1 (PAR1) antagonists. In the current study, we prepared a series of trans‐fused 5,5‐difulorooctahydroindenes which do not have a C5 stereogenic center, and evaluated their biological activities and metabolic stabilities. Compound 19 in this series, containing a spirooxazolidinone moiety at C2, showed excellent efficacy in both PAR1 binding (IC50 = 70 nM) and human platelet rich plasma (PRP) aggregation (IC50 = 0.19 μM), along with good metabolic stability (R50 = 345.8, 337.2, and 43.4 min in human, rat, and monkey liver microsomes, each), which is comparable to that of vorapaxar. Four stereoisomers of 19 were prepared and evaluated. (1S,2R,3aR,7aR)‐5,5‐Difluoro‐1‐[(E)‐2‐[5‐(3‐fluorophenyl)pyridin‐2‐yl]vinyl]octahydrospiro(indene‐2,5′‐oxazolidin)‐2′‐one (31) was found to be the most active (IC50 = 21 nM) stereoisomer as PAR1 antagonist. Compound 31 exhibited good in vivo oral PK profiles and significant ex vivo antithrombotic efficacy in cynomolgus monkeys upon oral administration. When the plasma concentration of 31 was maintained above 200 ng/mL, platelet aggregation induced by haTRAP was completely inhibited. [ABSTRACT FROM AUTHOR]