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

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