Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity.
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Porcelli L, Gilardi F, Laghezza A, Piemontese L, Mitro N, Azzariti A, Altieri F, Cervoni L, Fracchiolla G, Giudici M, Guerrini U, Lavecchia A, Montanari R, Di Giovanni C, Paradiso A, Pochetti G, Simone GM, Tortorella P, Crestani M, Loiodice F
Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity.
J Med Chem. 2012 Jan 12;55(1):37-54. doi: 10.1021/jm201306q. Epub 2011 Dec 2.
- PubMed ID
- 22081932 [ View in PubMed]
- Abstract
A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARgamma-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARgamma target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARalpha target genes indicating that their in vivo effects stemmed from an activation of both PPARalpha and gamma. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) {4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy}acetic acid Peroxisome proliferator-activated receptor delta EC 50 (nM) 21 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 20 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor gamma Ki (nM) 74 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor gamma Kd (nM) 120 N/A N/A Details