title: Trans-fused 5-[(tert-Butoxtycarbonyl)amino]octahydroindenes as a protease activated receptor-1 (PAR1) antagonist.
abstract: Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We designed and synthesized substituted analogues of octahydroindenes at C5 or C6 aiming to improvement of metabolic stability, and identified that trans-fused 5-[(tert-butoxtycarbonyl)amino]octahydroindene analogues showed improved metabolic stability with maintaining good activity on PAR1. Especially, 2-methanesulfonate 57 (IC50 = 0.006 μM; R50 = 126.3 min in human, 83.3 min in rat), sulfamate 58 (IC50 = 0.020 μM; R50 = 52.8 min in human, 106.0 min in rat), and N-(cyclopropyl)methylsufonamide 63 (IC50 = 0.010 μM; R50 = 51.4 min in human, 90.5 min in rat) exhibited excellent activity and metabolic stability both on human and rat liver microsomes, comparable to those obtained for varapaxar (IC50 = 0.0015 μM; R50 = 83.2 min in human, 32.4 min in rat). Additionally, these compounds (57, 58, and 63) represented significant efficacy (IC50 = 0.0022, 0.0062, and 0.015 μM, each) in human washed platelet aggregation (WPA) assay without cytotoxicity and CYP3A4 inhibitory activity.
authors.affiliation: Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.|Korea University of Science and Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.
authors.forename: Songhyun
authors.initials: S
authors.lastname: Baek
authors.affiliation: Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.|Department of Chemistry, Chungbuk National University, Chungdae-ro, Seowon-gu, Cheongju-si, 28644, Chungbuk, Republic of Korea.
authors.forename: Seongwoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Song
authors.affiliation: Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea. leesk@krict.re.kr.|Korea University of Science and Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea. leesk@krict.re.kr.
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Chungbuk National University, Chungdae-ro, Seowon-gu, Cheongju-si, 28644, Chungbuk, Republic of Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
chemical_list: D011480:Protease Inhibitors; D044463:Receptor, PAR-1; D010975:Platelet Aggregation Inhibitors
keywords: 6/5 fused bicycle; Metabolic stability; PAR1 binding; Platelet aggregation; Protease activated receptor 1; trans-fused 5-[(tert-Butoxtycarbonyl)amino]octahydroindene