Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation

Thiazolidinedione
PPARγ 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 PPARγ, whereas the side effects are
linked to classical PPARγ agonism. Thus compounds that inhibit
PPARγ Ser273 phosphorylation but lack classical PPARγ
agonism have been sought as safer antidiabetic therapies. Herein we
report the discovery by virtual screening of 10, which
is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated
phosphorylation of PPARγ Ser273 and displays negligible PPARγ
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.