A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor γ-activating properties

Thiazolidinediones (TZDs) constitute an exciting new class of antidiabetic compounds, which function as activating ligands for peroxisome proliferator-activated receptor γ (PPARγ). Until now, there has been an excellent correlation between in vivo hypoglycemic potency and in vitro binding and activation of PPARγ by TZDs. We have characterized MCC-555, a novel thiazolidinedione ligand for PPARγ with unique functional properties. The antidiabetic potency of this compound is greater than that of other TZDs, including BRL49653, yet its binding affinity for PPARγ is less than 1/10 that of BRL49653. The effect of MCC-555 binding on PPARγ transcriptional activity is highly context-specific such that it can function as a full agonist, partial agonist, or antagonist depending on the cell type or DNA binding site. These transcriptional properties are partly explained by unique partial agonism of coactivator recruitment to PPARγ. The properties of MCC- 555 are mechanistically distinct from those of the estrogen receptor partial agonist and antagonist tamoxifen because the N terminus of PPARγ is not required for activation by MCC-555, and MCC-555 does not stimulate corepressor recruitment to PPARγ. The context selectivity of MCC-555 may contribute to its enhanced hypoglycemic potency in vivo despite reduced affinity for PPARγ relative to other TZDs.