Identification of the First PPARα/γ Dual Agonist Able To Bind to Canonical and Alternative Sites of PPARγ and To Inhibit Its Cdk5-Mediated Phosphorylation

A new
series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPARα and γ
subtypes. X-ray studies in PPARγ 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 PPARγ antagonist and supported from
docking experiments. This compound did not activate the PPARγ-dependent
program of adipocyte differentiation inducing a very less severe lipid
accumulation compared to rosiglitazone but increased the insulin-stimulated
glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ
at serine 273 that is currently considered the mechanism by which
some PPARγ partial agonists exert antidiabetic effects similar
to thiazolidinediones, without showing their typical side effects.
This is the first PPARα/γ 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.