Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus

doi:10.1016/j.ejmech.2021.113720

	Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus
	He, Yu-Long 1; Chen, Meng-Ting 2,3; Wang, Ting 2; Zhang, Ming-Ming 1; Li, Ying-Xia 1; Wang, He-Yao 2; Ding, Ning 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2021-11-15
卷号	224 页码:14
关键词	Type 2 diabetes mellitus Dual FABP4/5 inhibitors Anti-lipolytic and anti-inflammatory effects Metabolic stability Anti-diabetic activities
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2021.113720
通讯作者	Li, Ying-Xia(liyx417@fudan.edu.cn) ; Wang, He-Yao(hywang@simm.ac.cn) ; Ding, Ning(dingning@fudan.edu.cn)
英文摘要	Fatty acid-binding protein 4 (FABP4) and fatty acid-binding protein 5 (FABP5) are promising therapeutic targets for the treatment of various metabolic diseases. However, the weak potency, low selectivity over FABP3, or poor pharmacokinetic profiles of currently reported dual FABP4/5 inhibitors impeded further research. Here, we described the characterization of a series of dual FABP4/5 inhibitors with improved metabolic stabilities and physicochemical properties based on our previous studies. Among the compounds, D9 and E1 exhibited good inhibitory activities against FABP4/5 and favorable selectivity over FABP3 in vitro. In cell-based assays, D9 and E1 exerted a decrease of FABP4 secretion, a strong anti-lipolytic effect in mature adipocytes, and suppression of MCP-1 expression in THP-1 macrophages. Moreover, D9 and E1 possessed good metabolic stabilities in mouse hepatic microsomes and acceptable pharmacokinetics profiles in ICR mice. Further in vivo experiments showed that D9 and E1 could potently decrease serum FABP4 levels and ameliorate glucose metabolism disorders in obese diabetic db/db mice. These results demonstrated that D9 and E1 could serve as lead compounds for the development of novel anti-diabetic drugs. (C) 2021 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81973178] ; National Natural Science Foundation of China[81773576] ; National Key R&D Program of China[2018YFC0310905] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040336]
WOS关键词	ACID-BINDING PROTEIN ; INSULIN-SECRETION ; APOLIPOPROTEIN-E ; OBESITY ; AP2 ; ADIPOKINE ; GLUCOSE ; ATHEROSCLEROSIS ; METABOLISM ; MECHANISMS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000703110000049
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297539]
专题	中国科学院上海药物研究所
通讯作者	Li, Ying-Xia; Wang, He-Yao; Ding, Ning
作者单位	1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	He, Yu-Long,Chen, Meng-Ting,Wang, Ting,et al. Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,224:14.
APA	He, Yu-Long.,Chen, Meng-Ting.,Wang, Ting.,Zhang, Ming-Ming.,Li, Ying-Xia.,...&Ding, Ning.(2021).Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,224,14.
MLA	He, Yu-Long,et al."Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 224(2021):14.