A selective modulator of peroxisome proliferator-activated receptor gamma 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 PPARgamma modulation are required. Here we report the discovery and profiling of a new PPARgamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARgamma ligand binding site. It's R-enantiomer evolved as eutomer regarding PPARgamma activation with high eudysmic ratio. The new PPARgamma modulator revealed outstanding selectivity over the PPARalpha and PPARdelta subtypes and did not promote adipogenesis in primary human fibro-blasts discriminating it from established agonists.