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[摘要]：Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) activators have drawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize new PPAR gamma activators. With this in mind, we explored the pharmacophoric space of PPAR gamma using seven diverse sets of activators. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 20 physicochemical descriptors capable of accessing self-consistent and predictive quantitative structure activity relationship (QSAR) (r(71)(2) = 0.80, F = 270.3, r(LOO)(2) = 0.73, r(PRESS)(2) against 17 external test inhibitors = 0.67). Three orthogonal pharmacophores emerged in the QSAR equation and were validated by receiver operating characteristic (ROC) curves analysis. The models were then used to screen the national cancer institute (NCI) list of compounds. The highest-ranking hits were tested in vitro. The most potent hits illustrated EC(50) values of 15 and 224 nM. (C) 2011 Elsevier Masson SAS. All rights reserved. |
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