Optimization of P2Y(12) Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbarnoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties
文献类型：期刊论文
| 作者 | Kong, Deyu1,3; Xue, Tao3; Guo, Bin3 ; Cheng, Jianjun2; Liu, Shunyin1; Wei, Jianhai1; Lu, Zhengyu3; Liu, Haoran3; Gong, Guoqing5; Lan, Tian5
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2019-03-28 |
| 卷号 | 62期号:6页码:3088-3106 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b01971 |
| 通讯作者 | Hu, Wenhao(huwh9@mail.sysu.edu.cn) ; Yang, Yushe(ysyang@simm.ac.cn) |
| 英文摘要 | P2Y(12) antagonists are widely used as anti platelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y(12) antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 581 displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 581 showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 581 as a promising drug candidate. |
| WOS关键词 | PLATELET ACTIVATION ; MYOCARDIAL-INFARCTION ; RECEPTOR ; CLOPIDOGREL ; MECHANISMS ; PHARMACOLOGY ; PRETREATMENT ; MANAGEMENT ; THERAPIES ; SAR216471 |
| 资助项目 | National Natural Science Foundation of China[21332003] ; Program for Guangdong Introducing Innovative and Entrepreneurial Teams[2016ZT06Y337] ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2016262] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000463116900015 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/290090]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Hu, Wenhao; Yang, Yushe |
| 作者单位 | 1.East China Normal Univ, Sch Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200062, Peoples R China 2.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China 5.China Pharmaceut Univ, Sch Pharm, Dept Pharmacol, Nanjing 210009, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Kong, Deyu,Xue, Tao,Guo, Bin,et al. Optimization of P2Y(12) Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbarnoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(6):3088-3106. |
| APA | Kong, Deyu.,Xue, Tao.,Guo, Bin.,Cheng, Jianjun.,Liu, Shunyin.,...&Yang, Yushe.(2019).Optimization of P2Y(12) Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbarnoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties.JOURNAL OF MEDICINAL CHEMISTRY,62(6),3088-3106. |
| MLA | Kong, Deyu,et al."Optimization of P2Y(12) Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbarnoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties".JOURNAL OF MEDICINAL CHEMISTRY 62.6(2019):3088-3106. |
入库方式： OAI收割
来源：上海药物研究所
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