Structural biology-based exploration of subtype-selective agonists for peroxisome proliferator-activated receptors

Abstract

Progress in understanding peroxisome proliferator-activated receptor (PPAR) subtypes as nuclear receptors that have pleiotropic effects on biological responses has enabled the exploration of new subtype-selective PPAR ligands. Such ligands are useful chemical biology/pharmacological tools to investigate the functions of PPARs and are also candidate drugs for the treatment of PPAR-mediated diseases, such as metabolic syndrome, inflammation and cancer. This review summarizes our medicinal chemistry research of more than 20 years on the design, synthesis, and pharmacological evaluation of subtype-selective PPAR agonists, which has been based on two working hypoth-eses, the ligand superfamily concept and the helix 12 (H12) holding induction concept. X-ray crys-tallographic analyses of our agonists complexed with each PPAR subtype validate our working hy-potheses.