Received for publication March 21, 2006.
Revised October 27, 2006.
Accepted for publication October 31, 2006.

Sulfonylureas and Glinides Exhibit PPAR Activity: A Combined Virtual Screening and Biological Assay Approach

Abstract

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target PPAR improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPAR and exhibit PPAR agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPAR target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide) exhibit PPAR agonistic activity at concentrations comparable to those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPAR target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, since it provides evidence that drugs can be designed which target both the sulfonylurea receptor and PPAR. Targeting both receptors could increase pancreatic insulin secretion, as well as improve insulin resistance. Glinides, sulfonylureas and other acidified sulfonamides may be promising leads in the development of new PPAR agonists. In addition, we provide a unified concept of the PPAR binding ability of seemingly disparate compound classes.

Key words: PPARs, Thermodynamic and kinetic processes and modeling, Fluorescence techniques, Receptor binding studies, Regulation of gene expression, Receptor-mediated, Protein-binding