Design and Synthesis of Highly Active Peroxisome Proliferator-Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity

详细信息    查看全文

• 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：488-496
• 全文大小：1427K
• ISSN：1860-7187

文摘

Based on 3-(((4-(hexylamino)-2-methoxyphenyl)amino)sulfonyl)-2-thiophenecarboxylic acid methyl ester (ST247, compound 2), a recently described peroxisome proliferator-activated receptor (PPAR)β/δ-selective inverse agonist, we designed and synthesized a series of structurally related ligands. The structural modifications presented herein ultimately resulted in a series of ligands that display increased cellular activity relative to 2. Moreover, with methyl 3-(m>Nm>-(2-(2-ethoxyethoxy)-4-(hexylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (PT-S264, compound 9 u), biologically relevant plasma concentrations in mice were achieved. The compounds presented in this study will provide useful novel tools for future investigations addressing the role of PPARβ/δ in physiological and pathophysiological processes.