1,3-Diphenyl-1H-pyrazole derivatives as a new series of potent PPAR gamma partial agonists
- Choi, Jiwon; Park, Yunsun; Lee, Hui Sun; Yang, Young; Yoon, Sukjoon
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- PERGAMON-ELSEVIER SCIENCE LTD
- Pyrazole; Peroxisome proliferators-activated receptor (PPAR); Comparative molecular field analysis (CoMFA); Computer-aided drug discovery; Molecular docking; Binding mode analysis
- BIOORGANIC & MEDICINAL CHEMISTRY, v.18, no.23, pp.8315 - 8323
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- BIOORGANIC & MEDICINAL CHEMISTRY
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- 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.
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