The Antidiabetic PPARγ Ligands: An Update on Compounds in Development

A novel class of antidiabetic agents, the thiazolidinediones, was developed in the 70s and 80s by screening newly synthesized compounds for their ability to lower blood glucose in diabetic rodents. Three molecules from this class, troglitazone, rosiglitazone and pioglitazone, were ultimately approved for the treatment of patients with type II diabetes. Although these compounds were developed without an understanding of their molecular mechanism of action, by the early 90s evidence began to accumulate linking the thiazolidinediones the nuclear receptor PPARγ (NR1C3). It was ultimately demonstrated that these molecules were high affinity ligands of PPARγ and that they increased the transcriptional activity of the receptor. Although many questions remain, multiple lines of evidence now indicate that the antidiabetic activities of the thiazolidinediones are mediated by their direct interaction with the receptor and the subsequent modulation of PPARγ target gene expression. The knowledge that PPARγ ligands can improve insulin resistance in diabetics, coupled with the availability of rapid assays for the identification and characterization of nuclear receptor ligands, has led to a virtual explosion in the number of new PPARγ ligands that are under development as antidiabetic agents. In this article we will briefly review the biology of PPARγ, and then provide an update of new synthetic PPARγ ligands that are under investigation or in development as antidiabetic drugs.