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.
AUTHORS
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
- PMID: 27482618[PubMed].
ABSTRACT
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.