title: Importance of 5/6-aryl substitution on the pharmacological profile of 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid derived PPARγ agonists.
abstract: In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPARγ activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain. Partial agonists with higher potency than telmisartan or the lead were obtained with OH or Cl substituents at the phenyl ring. Molecular modeling suggested additional hydrogen or halogen bonds with Phe360 located at helix 7. It is assumed that these interactions fix helix 7, thereby promoting a partial agonist conformation of the receptor. The theoretical considerations correlate very well with the results from the luciferase transactivation assay using hPPARγ-LBD as well as those from a time-resolved fluorescent resonance energy transfer (TR-FRET) assay in which the coactivator (TRAP220, PGC-1α) recruitment and corepressor (NCoR1) release pattern was investigated.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Obermoser
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Mauersberger
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Czifersky
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Marina
authors.initials: M
authors.lastname: Lipova
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Siegl
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria. Electronic address: Ronald.Gust@uibk.ac.at.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D056971:Nuclear Receptor Co-Repressor 1 / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000077333:Telmisartan
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077333:Telmisartan
keywords: Coactivator recruitment; Molecular modeling; Peroxisome proliferator-activated receptor γ; Pharmacological profile; Transactivation assay