Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPAR gamma Phosphorylation

Thiazolidinedione PPAR gamma agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPAR gamma, whereas the side effects are linked to classical PPAR gamma agonism. Thus compounds that inhibit PPAR gamma Ser273 phosphorylation but lack classical PPAR gamma agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPAR gamma binder and in vitro inhibitor of the CDKS-mediated phosphorylation of PPAR gamma Ser273 and displays negligible PPAR gamma agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the ob/ob diabetic mouse model.