title: Design, synthesis, and structure-activity and structure-pharmacokinetic relationship studies of novel [6,6,5] tricyclic fused oxazolidinones leading to the discovery of a potent, selective, and orally bioavailable FXa inhibitor.
abstract: The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles. Druggability evaluation of compound 11a was undertaken and elicited positive outcomes. All results indicate that compound 11a is a promising drug candidate for the prevention and treatment of thromboembolic diseases in venous and arterial systems.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xue
authors.forename: Shi
authors.initials: S
authors.lastname: Ding
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.forename: Yuren
authors.initials: Y
authors.lastname: Zhou
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Heyao
authors.initials: H
authors.lastname: Wang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chu
authors.forename: Guoqing
authors.initials: G
authors.lastname: Gong
authors.forename: Yinye
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D023303:Oxazolidinones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D065427:Factor Xa Inhibitors; D023303:Oxazolidinones; D015951:Factor Xa