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

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

Graphical abstractA series of pirinixic acid derivatives were synthesized and evaluated as subtype-selective peroxisome proliferator-activated receptor (PPARγ) agonists and modulator by in vitro transactivation of human PPARs.Figure optionsDownload full-size imageDownload as PowerPoint slide