A Selective Modulator of Peroxisome Proliferator-Activated Receptor g with an Unprecedented Binding Mode

The nuclear peroxisome proliferator-activated receptor g has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARg modulation are required. Here, we report the discovery and profiling of a new PPARg modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARg ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARg activation with a high eudysmic ratio. The new PPARg modulator revealed outstanding selectivity over the PPARa and PPARd subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.