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Characterization of Telmisartan‐Derived PPARγ Agonists: Importance of Moiety Shift from Position 6 to 5 on Potency, Efficacy and Cofactor Recruitment
Author(s) -
Herbst Lena,
Goebel Matthias,
Bandholtz Sebastian,
Gust Ronald,
Kintscher Ulrich
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200337
Subject(s) - chemistry , telmisartan , agonist , benzofuran , moiety , partial agonist , receptor , peroxisome proliferator activated receptor , pharmacology , stereochemistry , biochemistry , biology , endocrinology , blood pressure
Selective modulation of the peroxisome proliferator‐activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure‐lowering properties, the AT 1 ‐receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure–activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4 ‐ 5 and 4 ‐ 6 ), benzothiophene (agonists 5 ‐ 5 and 5 ‐ 6 ) or benzofuran (agonists 6 ‐ 5 and 6 ‐ 6 ) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC 50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3‐L1 cells and a luciferase assay with COS‐7 cells transiently transfected with pGal4‐hPPARgDEF, pGal5‐TK‐pGL3 and pRL‐CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC‐1 and PGC‐1α, and release of corepressor NCoR1 determined by time‐resolved fluorescence resonance energy transfer (TR‐FRET) was detected depending on residues in position 5 or 6.