Cover Picture: Design and Synthesis of Highly Active Peroxisome Proliferator-Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity (ChemMedChem 5/2016)
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- 作者：Dr. Philipp M. Toth ; Dr. Sonja Lieber ; Dr. Frithjof M. Scheer ; Tim Schumann ; Dr. Yvonne Schober ; Dr. Wolfgang A. Nockher ; Dr. Till Adhikary ; Dr. Sabine Mü ; ller-Brü ; sselbach ; Prof. Dr. Rolf Mü ; ller and Prof. Dr. Wibke E. Diederich
- 关键词：inverse agonists ; nuclear receptors ; PPAR&beta ; /&delta ; ST247 ; structure&ndash ; activity relationships
- 刊名：ChemMedChem
- 出版年：2016
- 出版时间：March 4, 2016
- 年：2016
- 卷：11
- 期：5
- 页码：445
- 全文大小：576K
- ISSN：1860-7187
文摘
The front cover picture shows the development of the inverse PPARβ/δ agonist methyl 3-(N-(2-(2-ethoxyethoxy)-4-(hexylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (PT-S264, 9u, shown centered). Inspired by the X-structure of the fatty acid eicosapentaenoic acid in complex with the PPARβ/δ ligand-binding domain, we envisioned that Y-shaped ligands (orange Y) would most likely better mimic the binding cleft, thus leading to a series of compounds displaying increased potency. To optimize the solubility of the compounds with respect to assay conditions, the introduction of an additional oxygen (orange O) in the newly incorporated side chain finally led to 9u, one of the most potent inverse PPARβ/δ agonists described so far. Furthermore, 9u displayed prolonged cellular activity and, moreover, biologically relevant plasma concentrations in mice could be achieved. More information can be found in the Full Paper by Wibke E. Diederich et al. on page 488 in Issue 5, 2016 (DOI: 10.1002/cmdc.201500594).