Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2

doi:10.1021/acs.jmedchem.7b01530

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	Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2
	Liu, Qiufeng 1,2,4; Huang, Fubao 3,4; Yuan, Xiaojing 2,4; Wang, Kai 3; Zou, Yi 2; Shen, Jianhua3 ; Xu, Yechun2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-12-28
卷号	60 期号:24 页码:10231-10244
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b01530
文献子类	Article
英文摘要	Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
资助项目	National Key R&D Program of China[2016YFA0502301] ; National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[81422047] ; National Natural Science Foundation of China[81661148046] ; National Natural Science Foundation of China[81602963] ; National Natural Science Foundation of China[81673302]
WOS关键词	ACTIVATING-FACTOR ACETYLHYDROLASE ; ZINC-DEPENDENT INHIBITORS ; DIABETIC MACULAR EDEMA ; A(2) LP-PLA(2) ; DARAPLADIB ; DISEASE ; EVENTS ; HEPATOCYTES ; SUPERFAMILY ; BINDING
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000419263400021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272350]
专题	药物发现与设计中心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
通讯作者	Shen, Jianhua; Xu, Yechun
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Liu, Qiufeng,Huang, Fubao,Yuan, Xiaojing,et al. Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(24):10231-10244.
APA	Liu, Qiufeng.,Huang, Fubao.,Yuan, Xiaojing.,Wang, Kai.,Zou, Yi.,...&Xu, Yechun.(2017).Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.JOURNAL OF MEDICINAL CHEMISTRY,60(24),10231-10244.
MLA	Liu, Qiufeng,et al."Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2".JOURNAL OF MEDICINAL CHEMISTRY 60.24(2017):10231-10244.