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

doi:10.1021/jm501045e

	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, Tao 1; Ding, Shi 1; Guo, Bin1 ; Zhou, Yuren 1; Sun, Peng 1; Wang, Heyao1 ; Chu, Wenjing 1; Gong, Guoqing 2; Wang, Yinye 3; Chen, Xiaoyan1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2014-09-25
卷号	57 期号:18 页码:7770-7791
ISSN号	0022-2623
DOI	10.1021/jm501045e
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[21372236] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301001-001] ; Science and Technology Commission of Shanghai Municipality[13431900402]
WOS关键词	FACTOR-XA INHIBITOR ; IN-VITRO ; ANTITHROMBOTIC AGENT ; HIGHLY POTENT ; RAT MODELS ; RIVAROXABAN ; APIXABAN ; ASSOCIATION ; THROMBOSIS ; PROFILES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000342396200021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276895]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Guo, Bin
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.