N-(5-substituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators

被引：10

作者：

Liu, Zhiqing ^{[2
]}

Zhu, Qingzhang ^{[1
]}

Li, Fuying ^{[2
]}

Zhang, Lina ^{[1
]}

Leng, Ying ^{[1
]}

Zhang, Ao ^{[2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Synthet Organ & Med Chem Lab SOMCL, Shanghai 201203, Peoples R China

来源：

MEDCHEMCOMM | 2011年 / 2卷 / 06期

基金：

美国国家科学基金会;

关键词：

GLUCOSE; METABOLISM; DISCOVERY; ABILITY;

D O I：

10.1039/c1md00002k

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel arylacetamides were designed to further explore the GK binding property at the aminothiazole C5 position. The C5-amide substituted aminothiazoles 7a-f generally displayed decreased potency, whereas most of the C5-triazole substituted aminothiazoles retained good GK potency. Triazole 15 with a hydroxyethyl side chain was the most potent among the current series possessing an EC50 value of 0.18 mu M. Its R-enantiomer R-15 showed similar potency (0.22 mu M) that deserves for further evaluation.

引用

页码：531 / 535

页数：5

共 35 条

[1] Glucokinase and molecular aspects of liver glycogen metabolism [J].

Agius, Loranne .

BIOCHEMICAL JOURNAL, 2008, 414 :1-18

[2] ALCL3-N,N-DIMETHYLANILINE - A NEW BENZYL AND ALLYL ETHER CLEAVAGE REAGENT [J].

AKIYAMA, T ;

HIROFUJI, H ;

OZAKI, S .

TETRAHEDRON LETTERS, 1991, 32 (10) :1321-1324

[3]

[Anonymous], GLUCOKINASE ITS REGU

[4] Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism - Evidence for a defect in haptic glucokinase activity [J].

Basu, A ;

Basu, R ;

Shah, P ;

Vella, A ;

Johnson, CM ;

Nair, KS ;

Jensen, MD ;

Schwenk, WF ;

Rizza, RA .

DIABETES, 2000, 49 (02) :272-283

[5] SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides:: Discovery of PSN-GK1 [J].

Bertram, Lisa S. ;

Black, Daniel ;

Briner, Paul H. ;

Chatfield, Rosemary ;

Cooke, Andrew ;

Fyfe, Matthew C. T. ;

Murray, P. John ;

Naud, Frederic ;

Nawano, Masao ;

Procter, Martin J. ;

Rakipovski, Guenaj ;

Rasamison, Chrystelle M. ;

Reynet, Christine ;

Schofield, Karen L. ;

Shah, Vilas K. ;

Spindler, Felix ;

Taylor, Amanda ;

Turton, Roy ;

Williams, Geoffrey M. ;

Wong-Kai-In, Philippe ;

Yasuda, Kosuke .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (14) :4340-4345

[6]

BRINER PH, Patent No. 2006016178

[7]

CHAPPELL MD, Patent No. 2006086488

[8] Glucokinase activators in diabetes management [J].

Coghlan, Matthew ;

Leighton, Brendan .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2008, 17 (02) :145-167

[9] 2-aminothiazole as a novel kinase inhibitor template.: Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor [J].

Das, Jagabandhu ;

Chen, Ping ;

Norris, Derek ;

Padmanabha, Ramesh ;

Lin, James ;

Moquin, Robert V. ;

Shen, Zhongqi ;

Cook, Lynda S. ;

Doweyko, Arthur M. ;

Pitt, Sidney ;

Pang, Suhong ;

Shen, Ding Ren ;

Fang, Qiong ;

de Fex, Henry F. ;

McIntyre, Kim W. ;

Shuster, David J. ;

Gillooly, Kathleen M. ;

Behnia, Kamelia ;

Schieven, Gary L. ;

Wityak, John ;

Barrish, Joel C. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (23) :6819-6832

[10] A novel glucokinase activator modulates pancreatic islet and hepatocyte function [J].

Efanov, AM ;

Barrett, DG ;

Brenner, MB ;

Briggs, SL ;

Delaunois, A ;

Durbin, JD ;

Giese, U ;

Guo, HH ;

Radloff, M ;

Gil, GS ;

Sewing, S ;

Wang, Y ;

Weichert, A ;

Zaliani, A ;

Gromada, J .

ENDOCRINOLOGY, 2005, 146 (09) :3696-3701

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