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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
Xue, Tao1; Ding, Shi1; Guo, Bin1; Zhou, Yuren1; Sun, Peng1; Wang, Heyao1; Chu, Wenjing1; Gong, Guoqing2; Wang, Yinye3; Chen, Xiaoyan1; Yang, Yushe1
刊名JOURNAL OF MEDICINAL CHEMISTRY
2014-09-25
DOI10.1021/jm501045e
57期:18页:7770-7791
收录类别SCI ; IC
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Medicinal
资助者National Natural Science Foundation of China ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" ; Science and Technology Commission of Shanghai Municipality ; National Natural Science Foundation of China ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" ; Science and Technology Commission of Shanghai Municipality
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]FACTOR-XA INHIBITOR ; IN-VITRO ; ANTITHROMBOTIC AGENT ; HIGHLY POTENT ; RAT MODELS ; RIVAROXABAN ; APIXABAN ; ASSOCIATION ; THROMBOSIS ; PROFILES
英文摘要

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.

语种英语
所属项目编号21372236 ; 2012ZX09301001-001 ; 13431900402
资助者National Natural Science Foundation of China ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" ; Science and Technology Commission of Shanghai Municipality ; National Natural Science Foundation of China ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" ; Science and Technology Commission of Shanghai Municipality
WOS记录号WOS:000342396200021
引用统计
被引频次:16[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/61446
专题北京大学药学院
作者单位1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.China Pharmaceut Univ, Dept Pharmacol, Sch Pharm, Nanjing 210009, Jiangsu, Peoples R China
3.Peking Univ, Dept Mol & Cellular Pharmacol, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Xue, Tao,Ding, Shi,Guo, Bin,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2014,57(18):7770-7791.
APA Xue, Tao.,Ding, Shi.,Guo, Bin.,Zhou, Yuren.,Sun, Peng.,...&Yang, Yushe.(2014).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.JOURNAL OF MEDICINAL CHEMISTRY,57(18),7770-7791.
MLA Xue, Tao,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 57.18(2014):7770-7791.
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