Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

doi:10.1021/jm301071h

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists
	Duan, Hongliang; Ning, Mengmeng; Chen, Xiaoyan; Zou, Qingan; Zhang, Liming; Feng, Ying; Zhang, Lina; Leng, Ying; Shen, Jianhua
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-12-13
卷号	55 期号:23 页码:10475-10489
ISSN号	0022-2623
DOI	10.1021/jm301071h
文献子类	Article
英文摘要	4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.
资助项目	National Science and Technology Major Project - Key New Drug Creation and Manufacturing Program, China[2012ZX09103101-049]
WOS关键词	BILE-ACID RECEPTOR ; TYPE-2 DIABETES-MELLITUS ; METABOLITE ; SECRETION ; MICE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000312227300014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277844]
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	Leng, Ying
作者单位	Chinese Acad Sci, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Duan, Hongliang,Ning, Mengmeng,Chen, Xiaoyan,et al. Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(23):10475-10489.
APA	Duan, Hongliang.,Ning, Mengmeng.,Chen, Xiaoyan.,Zou, Qingan.,Zhang, Liming.,...&Shen, Jianhua.(2012).Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists.JOURNAL OF MEDICINAL CHEMISTRY,55(23),10475-10489.
MLA	Duan, Hongliang,et al."Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists".JOURNAL OF MEDICINAL CHEMISTRY 55.23(2012):10475-10489.