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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]

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