title: Design and Synthesis of Highly Active Peroxisome Proliferator-Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity.
abstract: 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.
authors: Institut für Pharmazeutische Chemie, Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Philipp M
authors: PM
authors: Toth
authors: Institut für Molekularbiologie und Tumorforschung (IMT), Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Sonja
authors: S
authors: Lieber
authors: Institut für Pharmazeutische Chemie, Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Frithjof M
authors: FM
authors: Scheer
authors: Institut für Molekularbiologie und Tumorforschung (IMT), Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Tim
authors: T
authors: Schumann
authors: Institut für Laboratoriumsmedizin und Pathobiochemie, Molekulare Diagnostik, Philipps-Universität Marburg, Baldingerstraße, 35043, Marburg, Germany.
authors: Yvonne
authors: Y
authors: Schober
authors: Institut für Laboratoriumsmedizin und Pathobiochemie, Molekulare Diagnostik, Philipps-Universität Marburg, Baldingerstraße, 35043, Marburg, Germany.|Core Facility Metabolomics, Philipps-Universität Marburg, Baldingerstraße, 35043, Marburg, Germany.
authors: Wolfgang A
authors: WA
authors: Nockher
authors: Institut für Molekularbiologie und Tumorforschung (IMT), Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Till
authors: http://orcid.org/0000-0003-1951-5605
authors: T
authors: Adhikary
authors: Institut für Molekularbiologie und Tumorforschung (IMT), Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Sabine
authors: S
authors: Müller-Brüsselbach
authors: Institut für Molekularbiologie und Tumorforschung (IMT), Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany.
authors: Rolf
authors: R
authors: Müller
authors: Institut für Pharmazeutische Chemie, Zentrum für Tumor- und Immunbiologie (ZTI), Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany. wibke.diederich@staff.uni-marburg.de.|Core Facility Medicinal Chemistry, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043, Marburg, Germany. wibke.diederich@staff.uni-marburg.de.
authors: Wibke E
authors: http://orcid.org/0000-0001-5671-6575
authors: WE
authors: Diederich
mesh_terms: D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D047494:PPAR delta / Q000037:antagonists & inhibitors*; D048068:PPAR-beta / Q000037:antagonists & inhibitors*
chemical_list: D047494:PPAR delta; D048068:PPAR-beta
keywords: PPARβ/δ; ST247; inverse agonists; nuclear receptors; structure-activity relationships