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

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