Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors

被引：40

作者：

Chen, Xinde ^{[1
]}

Xu, Wenwei ^{[1
]}

Wang, Kai ^{[1
]}

Mo, Mingguang ^{[1
]}

Zhang, Wei ^{[1
]}

Du, Lili ^{[1
]}

Yuan, Xiaojing ^{[1
]}

Xu, Yechun ^{[1
]}

Wang, Yiping ^{[1
]}

Shen, Jianhua ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 21期

关键词：

PLATELET-ACTIVATING-FACTOR; ZINC-DEPENDENT INHIBITORS; LOW-DENSITY-LIPOPROTEIN; FACTOR ACETYLHYDROLASE; ACTIVE INHIBITORS; BIOLOGICAL EVALUATION; TRIAZOLE DERIVATIVES; DARAPLADIB; LP-PLA(2); DESIGN;

D O I：

10.1021/acs.jmedchem.5b01024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：8529 / 8541

页数：13

共 58 条

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