Skip to main content

Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin.


Temple KJKayla J , Duvernay MT Matthew T , Young SE Summer E , Wen W Wandong , Wu W Wenjun , Maeng JG Jae G , Blobaum AL Anna L , Stauffer SR Shaun R , Hamm HE Heidi E , Lindsley CW Craig W . Journal of medicinal chemistry. 2016 8 25; 59(16). 7690-5


Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 > 30 μM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 μM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.