Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema

doi:10.1021/acs.jmedchem.5b01930

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	Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A(2) (Lp-PLA(2)) Inhibitors as a Potential Therapy for Diabetic Macular Edema
	Chen, Xinde 1; Wang, Kai 1; Xu, Wenwei 1; Ma, Quanxin 2; Chen, Minli 2; Du, Lili 1; Mo, Mingguang 1; Wang, Yiping1 ; Shen, Jianhua1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	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.
资助项目	National Science and Technology Major Project "Key New Drug Creation and Manufacturing program"[2012ZX09103101-008]
WOS关键词	PLATELET-ACTIVATING-FACTOR ; ZINC-DEPENDENT INHIBITORS ; LOW-DENSITY-LIPOPROTEIN ; CORONARY-HEART-DISEASE ; FACTOR ACETYLHYDROLASE ; TRIAZOLE DERIVATIVES ; DARAPLADIB ; RISK ; BARRIER ; AMIDES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000372946500028
内容类型	期刊论文
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.