Characterization of new PPARgamma agonists: benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode.

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Goebel M, Wolber G, Markt P, Staels B, Unger T, Kintscher U, Gust R

Characterization of new PPARgamma agonists: benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode.

Bioorg Med Chem. 2010 Aug 15;18(16):5885-95. doi: 10.1016/j.bmc.2010.06.102. Epub 2010 Jul 3.

PubMed ID

20656494 [ View in PubMed

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Abstract

In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARgamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl)methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARgamma activation. An enhanced effect on PPARgamma activation could be observed if lipophilic moieties are introduced in these positions. 4'-[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC(50) of 0.26muM and the profile of a full agonist. Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pioglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	140	N/A	N/A	Details
Telmisartan	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	3400	N/A	N/A	Details