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Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor Activity: A Combined Virtual Screening and Biological Assay Approach

Biozentrum, University of Basel, Basel, Switzerland (M.S., M.P., A.R., T.S., U.A.M., C.R.); Swiss Institute of Bioinformatics, Basel, Switzerland (M.S., M.P., T.S.); Hoffmann-La Roche AG, Basel, Switzerland (A.R.); TheraSTrat AG, Allschwil, Switzerland (H.H.); DSM Nutritional Products, Human Nutrition and Health, Kaiseraugst, Switzerland (H.H.); Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands (S.K.); and BioFocus DPI, Allschwil, Switzerland (H.A.)

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (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 with 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, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPAR. Targeting both receptors could increase pancreatic insulin secretion and 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.

Address correspondence to: Marco Scarsi, Biozentrum, University of Basel, Klingelbergstr. 50-70, CH-4056 Basel, Switzerland. E-mail: marco.scarsi{at}unibas.ch