title: Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma 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 the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma 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 PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma 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 PPARgamma 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 PPARgamma. 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 PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstr. 50-70, CH-4056 Basel, Switzerland. marco.scarsi@unibas.ch
authors.forename: Marco
authors.initials: M
authors.lastname: Scarsi
authors.forename: Michael
authors.initials: M
authors.lastname: Podvinec
authors.forename: Adrian
authors.initials: A
authors.lastname: Roth
authors.forename: Hubert
authors.initials: H
authors.lastname: Hug
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.forename: Torsten
authors.initials: T
authors.lastname: Schwede
authors.forename: Urs A
authors.initials: UA
authors.lastname: Meyer
authors.forename: Christoph
authors.initials: C
authors.lastname: Rücker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000819:agonists; D003198:Computer Simulation; D003510:Cyclohexanes / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D005913:Glipizide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077205:Pioglitazone; D015221:Potassium Channels / Q000819:agonists; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists; D011485:Protein Binding; D011955:Receptors, Drug / Q000819:agonists; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D064233:Sulfonylurea Receptors; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D045162:Thiazolidinediones; D000077715:Nateglinide; D010649:Phenylalanine; C010969:gliquidone; D000077205:Pioglitazone; D005913:Glipizide