Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A(2) Inhibitors
文献类型：期刊论文
| 作者 | Chen, Xinde; Xu, Wenwei; Wang, Kai; Mo, Mingguang; Zhang, Wei; Du, Lili; Yuan, Xiaojing; Xu, Yechun ; Wang, Yiping; Shen, Jianhua
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2015-11-12 |
| 卷号 | 58期号:21页码:8529-8541 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acsjmedchem.5b01024 |
| 文献子类 | Article |
| 英文摘要 | Inhibition of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA(2) inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing. |
| WOS关键词 | ACTIVATING-FACTOR ACETYLHYDROLASE ; ZINC-DEPENDENT INHIBITORS ; LOW-DENSITY-LIPOPROTEIN ; ACTIVE INHIBITORS ; BIOLOGICAL EVALUATION ; TRIAZOLE DERIVATIVES ; LP-PLA(2) INHIBITORS ; MACULAR EDEMA ; DARAPLADIB ; ATHEROSCLEROSIS |
| 资助项目 | National Science and Technology Major Project "Key New Drug Creation and Manufacturing program"[2012ZX09103101-008] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000364796100014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276325]  |
| 专题 | 药理学第一研究室 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 药物发现与设计中心 |
| 通讯作者 | Wang, Yiping |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Xinde,Xu, Wenwei,Wang, Kai,et al. Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A(2) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2015,58(21):8529-8541. |
| APA | Chen, Xinde.,Xu, Wenwei.,Wang, Kai.,Mo, Mingguang.,Zhang, Wei.,...&Shen, Jianhua.(2015).Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A(2) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,58(21),8529-8541. |
| MLA | Chen, Xinde,et al."Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A(2) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 58.21(2015):8529-8541. |
入库方式： OAI收割
来源：上海药物研究所
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