Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

被引：44
作者：
Mao, Weiwei [2 ]
Ning, Mengmeng [1 ]
Liu, Zhiqing [2 ]
Zhu, Qingzhang [1 ]
Leng, Ying [1 ]
Zhang, Ao [2 ]
机构：
[1] Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
[2] Chinese Acad Sci, Synthet Organ & Med Chem Lab, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 09期
基金：
美国国家科学基金会;
关键词：
Type 2 diabetes (T2D); Glucokinase activator; Benzamide derivatives; Privileged-fragment-merging; Aminothiazole; INSULIN-RESISTANCE; DIABETES THERAPY; THIAZOL-2-YL)-2-ARYL-3-(TETRAHYDRO-2H-PYRAN-4-YL) PROPANAMIDES; METABOLIC-REGULATION; GLUCOSE; SECRETION; DISCOVERY; PARADIGM; EFFICACY; DISEASE;
D O I：
10.1016/j.bmc.2012.03.008
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 benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC50 values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2982 / 2991
页数：10
相关论文
共 41 条
[1]   Glucose effectiveness assessed under dynamic and steady state conditions - Comparability of uptake versus production components [J].
Ader, M ;
Ni, TC ;
Bergman, RN .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (06) :1187-1199
[2]  
[Anonymous], [No title captured], Patent No. 2006016178
[3]   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
[4]   Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes [J].
Bebernitz, Gregory R. ;
Beaulieu, Valerie ;
Dale, Bethany A. ;
Deacon, Richard ;
Duttaroy, Alokesh ;
Gao, Jiaping ;
Grondine, Melissa S. ;
Gupta, Ramesh C. ;
Kakmak, Mesut ;
Kavana, Michael ;
Kirman, Louise C. ;
Liang, Jinsheng ;
Maniara, Wieslawa M. ;
Munshi, Siralee ;
Nadkarni, Sunil S. ;
Schuster, Herbert F. ;
Stams, Travis ;
Denny, Irene St. ;
Taslimi, Paul M. ;
Vash, Brian ;
Caplan, Shari L. .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (19) :6142-6152
[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]  
Boyd S., 2003, World Patent Application, Patent No. [2003015774, WO 2003/015774]
[7]   Ullmann diaryl ether synthesis: Rate acceleration by 2,2,6,6-tetramethylheptane-3,5-dione [J].
Buck, E ;
Song, ZJ ;
Tschaen, D ;
Dormer, PG ;
Volante, RP ;
Reider, PJ .
ORGANIC LETTERS, 2002, 4 (09) :1623-1626
[8]  
Caulkett P, 2003, World Intellectual Property Organization, Patent No. [WO 2003000262, 2003000262]
[9]   Glucokinase activators in diabetes management [J].
Coghlan, Matthew ;
Leighton, Brendan .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2008, 17 (02) :145-167
[10]  
Corbett W.L., 2001, World Patent Application, Patent No. [WO 2001/44216, 200144216]
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