Apart from direct peroxisome proliferator-activated receptor γ (PPARγ) agonism, several PPARγ ligands have recently been shown to exert anti-diabetic effects through a second, distinct biochemical function: blocking the obesity-linked phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) at serine 273. This effect requires binding to the PPARγ ligand binding domain, which causes a conformational change that interferes with the ability of Cdk5 to phosphorylate serine 273. SR 1664 is a small molecule that blocks phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) by cyclin-dependent kinase 5 with an IC50 value of 80 nM (Ki = 28.7 nM) without exhibiting agonist activity at the PPARγ receptor. It demonstrates potent, dose-dependent anti-diabetic effects in obese mice without inducing fluid retention and weight gain or inhibiting bone formation.