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Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity
Author(s) -
Toth Philipp M.,
Lieber Sonja,
Scheer Frithjof M.,
Schumann Tim,
Schober Yvonne,
Nockher Wolfgang A.,
Adhikary Till,
MüllerBrüsselbach Sabine,
Müller Rolf,
Diederich Wibke E.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500594
Subject(s) - peroxisome , inverse agonist , peroxisome proliferator activated receptor , chemistry , agonist , receptor , biological activity , carboxylate , stereochemistry , biochemistry , pharmacology , biology , in vitro
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‐( N ‐(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.