Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 6, Pages 2011-2021Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.02.053
Keywords
3D-QSAR; Pentacyclic triterpenes; Glycogen phosphorylase
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Funding
- National Natural Science Foundation of China [20720102040, 20972174, 30672523, 91029704, 90713037]
- State Key Program of Basic Research of China [2009CB918502]
- National ST Major Project [2009ZX09501-001]
- Hi-Tech Research and Development program of China [2006AA020404]
- Shanghai Committee of Science and Technology [10410703900]
- Guangdong Science and Technology Department [2010A030100006]
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Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1 mu M. (C) 2011 Elsevier Masson SAS. All rights reserved.
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