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

doi:10.1021/acsjmedchem.5b01024

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	Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A(2) Inhibitors
	Chen, Xinde; Xu, Wenwei; Wang, Kai; Mo, Mingguang; Zhang, Wei; Du, Lili; Yuan, Xiaojing; Xu, Yechun; Wang, Yiping; Shen, Jianhua
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	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.
资助项目	National Science and Technology Major Project "Key New Drug Creation and Manufacturing program"[2012ZX09103101-008]
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
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000364796100014
内容类型	期刊论文
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.