title: (Z)-2-(2-bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172): an orally bioavailable PPARβ/δ-selective ligand with inverse agonistic properties.
abstract: The ligand-regulated nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a potential pharmacological target due to its role in disease-related biological processes. We used TR-FRET-based competitive ligand binding and coregulator interaction assays to screen 2693 compounds of the Open Chemical Repository of the NCI/NIH Developmental Therapeutics Program for inhibitory PPARβ/δ ligands. One compound, (Z)-3-(4-dimethylamino-phenyl)-2-phenyl-acrylonitrile, was used for a systematic SAR study. This led to the design of derivative 37, (Z)-2-(2-bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172), a novel PPARβ/δ-selective ligand showing high binding affinity (IC(50) = 27 nM) and potent inverse agonistic properties. 37 selectively inhibited the agonist-induced activity of PPARβ/δ, enhanced transcriptional corepressor recruitment, and down-regulated transcription of the PPARβ/δ target gene Angptl4 in mouse myoblasts (IC(50) = 9.5 nM). Importantly, 37 was bioavailable after oral application to mice with peak plasma levels in the concentration range of its maximal inhibitory potency, suggesting that 37 will be an invaluable tool to elucidate the functions and therapeutic potential of PPARβ/δ.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lieber
authors.forename: Frithjof
authors.initials: F
authors.lastname: Scheer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meissner
authors.forename: Simone
authors.initials: S
authors.lastname: Naruhn
authors.forename: Till
authors.initials: T
authors.lastname: Adhikary
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism; D054314:Drug Inverse Agonism; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D048068:PPAR-beta / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C573844:2-(2-bromophenyl)-3-((4-(1-methylpiperazine)amino)phenyl)acrylonitrile; D002843:Chromatin; D056970:Co-Repressor Proteins; D008024:Ligands; D047495:PPAR gamma; D048068:PPAR-beta; D010879:Piperazines; D054852:Small Molecule Libraries; D000181:Acrylonitrile