Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

doi:10.1016/j.ejmech.2017.07.051

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	Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation
	Wang, Zhengyu 3; Shi, Xiaofan 1,2; Zhang, Huan 4; Yu, Liang2 ; Cheng, Yanhua 3; Zhang, Hefeng 1,5; Zhang, Huibin 4; Zhou, Jinpei 2,3; Chen, Jing2 ; Shen, Xu
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-10-20
卷号	139 页码:128-152
关键词	Type 2 diabetes mellitus Hypoglycemia Dyslipidemia Glucokinase activators N-Thiazol-2-yl-benzamides
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.07.051
文献子类	Article
英文摘要	Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected beta-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	"Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040313] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120154035]
WOS关键词	TYPE-2 DIABETES-MELLITUS ; ALLOSTERIC ACTIVATORS ; CLINICAL CANDIDATE ; GLUCOSE-METABOLISM ; LIVER ; EFFICACY ; THERAPY ; MANAGEMENT ; INHIBITOR ; PSN-GK1
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:000412788200011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272443]
专题	药物安全性评价中心药物化学研究室
通讯作者	Zhou, Jinpei; Chen, Jing; Duan, Wenhu
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 3.China Pharmaceut Univ, Dept Med Chem, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 4.China Pharmaceut Univ, Ctr Drug Discovery, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wang, Zhengyu,Shi, Xiaofan,Zhang, Huan,et al. Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,139:128-152.
APA	Wang, Zhengyu.,Shi, Xiaofan.,Zhang, Huan.,Yu, Liang.,Cheng, Yanhua.,...&Duan, Wenhu.(2017).Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,139,128-152.
MLA	Wang, Zhengyu,et al."Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 139(2017):128-152.