1,3-Diphenyl-1H-pyrazole derivatives as a new series of potent PPARγ partial agonists

被引：23

作者：

Choi, Jiwon ^{[1
]}

Park, Yunsun ^{[1
]}

Lee, Hui Sun ^{[1
]}

Yang, Young ^{[1
]}

Yoon, Sukjoon ^{[1
]}

机构：

[1] Sookmyung Womens Univ, Dept Biol Sci, Seoul 140742, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 23期

关键词：

Pyrazole; Peroxisome proliferators-activated receptor (PPAR); Comparative molecular field analysis (CoMFA); Computer-aided drug discovery; Molecular docking; Binding mode analysis; ACTIVATED-RECEPTOR-GAMMA; SELECTIVE INHIBITOR; DRUG DESIGN; COMFA; IDENTIFICATION; DOCKING; QSAR; THIAZOLIDINEDIONES; OPTIMIZATION; TELMISARTAN;

D O I：

10.1016/j.bmc.2010.09.068

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

A new series of PPAR gamma partial agonists, 1,3-diphenyl-1H-pyrazole derivatives, were identified using an improved virtual screening scheme combining ligand-centric and receptor-centric methods. An in vitro assay confirmed the nanomolar binding affinity of 1,3-diphenyl-1H-pyrazole derivatives such as SP3415. We also characterized the competitive antagonism of SP3415 against rosiglitazone at micromolar concentrations. They showed a PPAR gamma partial agonistic activity similar to that of a known PPAR gamma drug, pioglitazone, in a cell-based transactivation assay. Furthermore, the structure-activity relationships of the pyrazole derivatives were investigated through comparative molecular field analysis and binding mode analysis, which provided new insight concerning their partial agonistic effect on PPAR gamma. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：8315 / 8323

页数：9

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