Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema
文献类型：期刊论文
| 作者 | Chen, Xinde1; Wang, Kai1; Xu, Wenwei1; Ma, Quanxin2; Chen, Minli2; Du, Lili1; Mo, Mingguang1; Wang, Yiping1 ; Shen, Jianhua1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2016-03-24 |
| 卷号 | 59期号:6页码:2674-2687 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5b01930 |
| 文献子类 | Article |
| 英文摘要 | Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA(2) inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA(2) in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA(2) inhibitors for prevention and/or treatment of DME. |
| WOS关键词 | PLATELET-ACTIVATING-FACTOR ; ZINC-DEPENDENT INHIBITORS ; LOW-DENSITY-LIPOPROTEIN ; CORONARY-HEART-DISEASE ; FACTOR ACETYLHYDROLASE ; TRIAZOLE DERIVATIVES ; DARAPLADIB ; RISK ; BARRIER ; AMIDES |
| 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:000372946500028 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276098]  |
| 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; Shen, Jianhua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Zhejiang Chinese Med Univ, Laboratory Anim Res Ctr, Hangzhou 310053, Zhejiang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Xinde,Wang, Kai,Xu, Wenwei,et al. Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(6):2674-2687. |
| APA | Chen, Xinde.,Wang, Kai.,Xu, Wenwei.,Ma, Quanxin.,Chen, Minli.,...&Shen, Jianhua.(2016).Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema.JOURNAL OF MEDICINAL CHEMISTRY,59(6),2674-2687. |
| MLA | Chen, Xinde,et al."Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema".JOURNAL OF MEDICINAL CHEMISTRY 59.6(2016):2674-2687. |
入库方式： OAI收割
来源：上海药物研究所
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