Structural Biology Inspired Development of a Series of Human Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Ligands: From Agonist to Antagonist

Recent progress in the structural and molecular pharmacological understanding of the nuclear receptor, peroxisome proliferator-activated receptor gamma (hPPARγ)—a transcription factor with pleiotropic effects on biological responses—has enabled the investigation of various graded hPPARγ ligands (full agonist, partial agonist, and antagonist). Such ligands are useful tools to investigate the functions of hPPARγ in detail and are also candidate drugs for the treatment of hPPARγ-mediated diseases, such as metabolic syndrome and cancer. This review summarizes our medicinal chemistry research on the design, synthesis, and pharmacological evaluation of a covalent-binding and non-covalent-binding hPPARγ antagonist, both of which have been created based on our working hypothesis of the helix 12 (H12) holding induction/inhibition concept. X-ray crystallographic analyses of our representative antagonists complexed with an hPPARγ ligand binding domain (LBD) indicated the unique binding modes of hPPARγ LBD, which are quite different from the binding modes observed for hPPARγ agonists and partial agonists.