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
文献类型：期刊论文
| 作者 | Xue, Tao1; Ding, Shi1; Guo, Bin1 ; Zhou, Yuren1; Sun, Peng1; Wang, Heyao1; Chu, Wenjing1; Gong, Guoqing2; Wang, Yinye3; Chen, Xiaoyan1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 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. |
| WOS关键词 | FACTOR-XA INHIBITOR ; IN-VITRO ; ANTITHROMBOTIC AGENT ; HIGHLY POTENT ; RAT MODELS ; RIVAROXABAN ; APIXABAN ; ASSOCIATION ; THROMBOSIS ; PROFILES |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000342396200021 |
| 出版者 | AMER CHEMICAL SOC |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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