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Discovery of Octahydroindenes as PAR1 Antagonists.

ABSTRACT: Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure-activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high potency and no significant cytotoxicity; however, the compounds were metabolically unstable in both human and rat liver microsomes. Current research efforts are focused on optimizing the compounds to improve metabolic stability and physicochemical properties as well as potency.

SUBMITTER: Lee S

PROVIDER: S-EPMC4027540 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Discovery of Octahydroindenes as PAR1 Antagonists.

Lee Sunkyung S Song Jong-Hwan JH Park Chul Min CM Kim Jin-Seok JS Jeong Ji-Hye JH Cho Woo-Young WY Lim Dong-Chul DC

ACS medicinal chemistry letters 20130910 11

Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure-activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high pot ...[more]

PMID: 24900604

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