Identification of the first PPARa/g able to bind to canonical and alternate sites of PPARg and to inhibit its Cdk-5-mediated phosphorylation

A new series of derivatives of the PPARa/g dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPARa and g subtypes. X-ray studies in PPARg revealed two different binding modes of (S)-6 to the canonical site. However, (S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPAR? antagonist and supported from docking experiments. This compound did not activate the PPARg-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulinstimulated glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPARg at serine 273 that is currently considered the mechanism by which some PPARg partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPAR?/? dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.