title: New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile.
abstract: In previous studies, the 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was identified as pharmacophoric core for PPARγ activation. In this structure-activity relationship study the C2-alkyl chain was elongated and the 2-COOH group was changed to a carbamide/carbonitrile or shifted to the 3- or 4-position. Furthermore, the benzo[d]imidazole was exchanged by 2,3-dihydrobenzo[d]thiazole or 1H-indole. C2-propyl derivatives showed the profile of partial agonists, while elongation of the C2-chain to that of an n-heptyl group or a 4-COOH shift changed the pharmacological profile to that of a potent full agonist. This finding can be explained by binding to the LBD in different ligand conformations. Two anchoring points (Tyr473 and Arg288) exist in the LBD, which have to be contacted to achieve receptor activation. In a crystal violet chemosensitivity assay using COS-7 cells and LNCaP cells expressing PPARγ only the carbamide derivatives influenced the cell growth, independently on the presence of the PPARγ. Therefore, receptor mediated cytotoxicity can be excluded.
authors: Pharmaceutical Chemistry, Institute of Pharmacy, Universität Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria.
authors: Victoria
authors: V
authors: Obermoser
authors: Pharmaceutical Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195, Berlin, Germany.
authors: Margarethe E
authors: ME
authors: Urban
authors: Computer-Aided Drug Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195, Berlin, Germany.
authors: Manuela S
authors: MS
authors: Murgueitio
authors: Computer-Aided Drug Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195, Berlin, Germany.
authors: Gerhard
authors: G
authors: Wolber
authors: Institute of Pharmacology, Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Hessische Str. 3-4, 10115, Berlin, Germany.
authors: Ulrich
authors: U
authors: Kintscher
authors: Pharmaceutical Chemistry, Institute of Pharmacy, Universität Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria. Electronic address: ronald.gust@uibk.ac.at.
authors: Ronald
authors: R
authors: Gust
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D051379:Mice; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000077333:Telmisartan; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D000077333:Telmisartan
keywords: Binding mode; Cytotoxicity; Molecular modeling; PPARγ; Transactivation