title: Octahydrocyclopenta[c]pyridine and octahydrocyclopenta[c]pyran analogues 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 have designed and synthesized fused 6/5 heterobicycle analogues with octahydrocyclopenta[c]pyridine or octahydrocyclopenta[c]pyran core scaffold by the insertion of heteroatom at C5 of octahydroindene ring aiming to improvement of metabolic stability. Both heterobicycle analogues showed much more improved metabolic stability compared with octahydroindenes without remarkable decrease in activity. Compounds 22 (IC50 = 110 nM) and 33 (IC50 = 50 nM) from this series showed good activity on PAR1 with moderate metabolic stability.
authors.affiliation: Division of Drug Discovery Research, Research Center for Medicinal Chemistry, 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: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: Division of Drug Discovery Research, Research Center for Medicinal Chemistry, 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: Haejin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Drug Discovery Research, Research Center for Medicinal Chemistry, 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: Division of Drug Discovery Research, Research Center for Medicinal Chemistry, 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: Division of Drug Discovery Research, Research Center for Medicinal Chemistry, 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
mesh_terms: D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism*; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D010975:Platelet Aggregation Inhibitors
chemical_list: D011714:Pyrans; D011725:Pyridines; D010975:Platelet Aggregation Inhibitors
keywords: 6/5 Fused heterobicycle; Metabolic stability; Octahydrocyclopenta[c]pyran; Octahydrocyclopenta[c]pyridine; Octahydroindene; Protease activated receptor 1