2. Academic Validation
  3. New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile

New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile

  • Eur J Med Chem. 2016 Nov 29:124:138-152. doi: 10.1016/j.ejmech.2016.08.027.
Victoria Obermoser 1,  Margarethe E Urban 2,  Manuela S Murgueitio 3,  Gerhard Wolber 3,  Ulrich Kintscher 4,  Ronald Gust 5
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry, Institute of Pharmacy, Universität Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria.
  • 2 Pharmaceutical Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195, Berlin, Germany.
  • 3 Computer-Aided Drug Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195, Berlin, Germany.
  • 4 Institute of Pharmacology, Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Hessische Str. 3-4, 10115, Berlin, Germany.
  • 5 Pharmaceutical Chemistry, Institute of Pharmacy, Universität Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria. Electronic address: ronald.gust@uibk.ac.at.
PMID: 27569195 DOI: 10.1016/j.ejmech.2016.08.027
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.

Keywords

Binding mode; Cytotoxicity; Molecular modeling; PPARγ; Transactivation.

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