Design, synthesis and. biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5 '-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes

doi:10.1016/j.ejmech.2017.09.012

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	Design, synthesis and. biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5 '-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes
	Zhou, Shengbin 1,2; Duan, Yanan 3; Wang, Jiang1,2 ; Zhang, Jin 3; Sun, Haifeng 1,2; Jiang, Haowen 3; Gu, Zhanni 1,2; Tong, Junhua 1,2; Li, Jingya1 ; Li, Jia1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-11-10
卷号	140 页码:448-464
关键词	Tetrahydroberberine 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines Mitochondrial respiration AMPK indirect activators db/db mice
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.09.012
文献子类	Article
英文摘要	A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2'3,4]pyrido[1,2-b]isoquino-lines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60-85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db/db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC50 > 10 mu M). (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81470166] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; Shanghai Commission of Science and Technology[14431905400]
WOS关键词	TETRAHYDROPROTOBERBERINE DERIVATIVES ; DOPAMINE D-1 ; BERBERINE ; MELLITUS ; MICE ; PREVALENCE ; INHIBITORS ; IDENTIFICATION ; ABSORPTION ; EFFICACY
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:000414620000033
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272406]
专题	国家新药筛选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药物化学研究室药物安全性评价中心
通讯作者	Li, Jia; Liu, Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.East China Normal Univ, Coll Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Shengbin,Duan, Yanan,Wang, Jiang,et al. Design, synthesis and. biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5 '-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,140:448-464.
APA	Zhou, Shengbin.,Duan, Yanan.,Wang, Jiang.,Zhang, Jin.,Sun, Haifeng.,...&Liu, Hong.(2017).Design, synthesis and. biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5 '-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,140,448-464.
MLA	Zhou, Shengbin,et al."Design, synthesis and. biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3 ',2 ':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5 '-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 140(2017):448-464.