Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 11, Pages 1054-1058Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400235c
Keywords
Octahydroindene; PAR1 antagonist; PRP aggregation; antiplatelet; bleeding
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Funding
- Global Frontier Project [NRF-2011-0032185]
- center for Biological Modulator of the 21st century Frontier R&D program by the Ministry of Science, ICT, and Future Planning of Korea
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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.
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