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Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators

文献类型：期刊论文

作者Li, Fuying2; Zhu, Qingzhang1; Zhang, Yi2; Feng, Ying1; Leng, Ying1; Zhang, Ao2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2010-06-01
卷号18期号:11页码:3875-3884
关键词Type 2 diabetes (T2D) Glucokinase activator Arylacetamide Aminothiazole
ISSN号0968-0896
DOI10.1016/j.bmc.2010.04.038
文献子类Article
英文摘要A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC(50) of 0.026 mu M. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new antidiabetic treatment. (C) 2010 Elsevier Ltd. All rights reserved.
WOS关键词INSULIN-RESISTANCE ; DIABETES THERAPY ; METABOLIC-REGULATION ; GLYCOGEN-METABOLISM ; GLUCOSE-METABOLISM ; TYPE-2 ; DISCOVERY ; HEPATOCYTES ; MANAGEMENT ; SECRETION
资助项目Chinese National Science Foundation[30772625] ; National Basic Research Program of China[2009CB522300] ; National Science & Technology Major Project, China[2009ZX09301-001] ; National Science & Technology Major Project, China[2009ZX09103-062] ; 863 grant[2007AA022163] ; Chinese Academy of Sciences[00000000]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000278078600028
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/278881]  
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
药物化学研究室
通讯作者Leng, Ying
作者单位1.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, SIMM, SOMCL, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Fuying,Zhu, Qingzhang,Zhang, Yi,et al. Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2010,18(11):3875-3884.
APA Li, Fuying,Zhu, Qingzhang,Zhang, Yi,Feng, Ying,Leng, Ying,&Zhang, Ao.(2010).Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators.BIOORGANIC & MEDICINAL CHEMISTRY,18(11),3875-3884.
MLA Li, Fuying,et al."Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators".BIOORGANIC & MEDICINAL CHEMISTRY 18.11(2010):3875-3884.

入库方式： OAI收割

来源：上海药物研究所

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