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 KJ, Duvernay MT, Young SE, Wen W, Wu W, Maeng JG, Blobaum AL, Stauffer SR, Hamm HE, Lindsley CW
J Med Chem. 2016 59 (16): 7690-5

PMID: 27482618 · PMCID: PMC5775816 · DOI:10.1021/acs.jmedchem.6b00928

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.

MeSH Terms (9)

Dose-Response Relationship, Drug Enzyme Inhibitors Humans Indoles Molecular Structure Pyrimidines Receptors, Thrombin Structure-Activity Relationship Thrombin

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