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
    Ader, M
    Ni, TC
    Bergman, RN
    [J]. 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
    Basu, A
    Basu, R
    Shah, P
    Vella, A
    Johnson, CM
    Nair, KS
    Jensen, MD
    Schwenk, WF
    Rizza, RA
    [J]. DIABETES, 2000, 49 (02) : 272 - 283
  • [4] Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes
    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.
    [J]. 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
    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
    [J]. 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
    Buck, E
    Song, ZJ
    Tschaen, D
    Dormer, PG
    Volante, RP
    Reider, PJ
    [J]. 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
    Coghlan, Matthew
    Leighton, Brendan
    [J]. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2008, 17 (02) : 145 - 167
  • [10] Corbett W.L., 2001, World Patent Application, Patent No. [WO 2001/44216, 200144216]
12345