The therapeutic effects of antidiabetic PPARγ ligands were believed to be mediated solely through agonism of this receptor. However, substantial insulin-sensitizing activity is observed with both full and partial PPARγ agonists. Providing a possible explanation for this, a second biochemical function of many antidiabetic PPARγ ligands has emerged — blockade of the obesity-linked phosphorylation of PPARγ by cyclin-dependent kinase 5 (CDK5) at Ser273. Recent observations suggest that this may be linked to the clinical effects of TZDs. With this in mind, Choi et al. hypothesized that it might be possible to develop a new class of PPARγ-targeted antidiabetic drugs.
First, the authors developed a series of analogues based on a compound previously reported to be an extremely potent and selective PPARγ partial agonist. Optimization for high-affinity PPARγ binding, blockade of CDK5-mediated PPARγ phosphorylation and a lack of classical agonist activity led to the identification of SR1664, which exhibited relatively desirable pharmacokinetic properties. Further analysis revealed that the non-agonist actions of SR1664 were likely to be due to its ability to increase the conformational mobility of the carboxy-terminal end of the H11 helix of the PPARγ ligand-binding domain — in contrast to agonists, which affect crucial hydrogen bonds within the C-terminal helix (H12) to stabilize the AF2 surface, thereby facilitating co-activator interactions.
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