A selective modulator of peroxisome proliferator-activated receptor γ with unprecedented binding mode.

The nuclear peroxisome proliferator-activated receptor gamma 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 PPAR gamma modulation are required. Here, we report the discovery and profiling of a new PPAR gamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPAR. ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPAR. activation with a high eudysmic ratio. The new PPAR gamma modulator revealed outstanding selectivity over the PPAR alpha and PPAR delta subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.