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

Bioorganic & Medicinal Chemistry
Matthias GoebelRonald Gust

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...Continue Reading

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Citations

Feb 24, 2012·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Yasushi AmanoMakoto Takeuchi
Sep 24, 2015·ACS Medicinal Chemistry Letters·Alice AsteianTheodore M Kamenecka
Aug 30, 2016·European Journal of Medicinal Chemistry·Victoria ObermoserRonald Gust
Oct 16, 2019·American Journal of Respiratory and Critical Care Medicine·Michael D KimMatthias Salathe
Jul 28, 2021·Journal of Medicinal Chemistry·Xiangqian LiDayong Shi

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