title: 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.
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Song
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: R&D Park, LG Life Sciences , 104-1 Munji-Dong, Yuseong, Deajeon 305-380, Korea.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Cho
authors.affiliation: R&D Park, LG Life Sciences , 104-1 Munji-Dong, Yuseong, Deajeon 305-380, Korea.
authors.forename: Dong-Chul
authors.initials: DC
authors.lastname: Lim
keywords: Octahydroindene; PAR1 antagonist; PRP aggregation; antiplatelet; bleeding