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学科主题: 药学
题名:
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
作者: 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
发表日期: 2014-09-25
DOI: 10.1021/jm501045e
卷: 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
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
项目资助者: 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
WOS记录号: WOS:000342396200021
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/61446
Appears in Collections:北京大学药学院_期刊论文

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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

Recommended Citation:
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.
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