Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator.

Theresa M Thieme, Ramona Steri, Ewgenij Proschak, Alexander Paulke, Gisbert Schneider, Manfred Schubert-Zsilavecz

Institute of Pharmaceutical Chemistry, ZAFES/LiFF/FIRST, Goethe-University Frankfurt, 60438 Frankfurt, Germany. schubert-zsilavecz@pharmchem.uni-frankfurt.de

Bioorganic & medicinal chemistry letters 2010 Apr 15

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Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in glucose and lipid homeostasis. PPARgamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARgamma modulators (SPPARgammaMs) was developed, which are believed to show less side effects than full PPARgamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPARalpha and PPARgamma, leads to low micromolar active balanced dual agonists of PPARalpha and PPARgamma. Herein we present modifications of pirinixic acid leading to subtype-selective PPARgamma agonists and furthermore the development of a selective PPARgamma modulator guided by molecular docking studies. Copyright 2010 Elsevier Ltd. All rights reserved.

Citation

Theresa M Thieme, Ramona Steri, Ewgenij Proschak, Alexander Paulke, Gisbert Schneider, Manfred Schubert-Zsilavecz. Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator. Bioorganic & medicinal chemistry letters. 2010 Apr 15;20(8):2469-73