title: Characterization of telmisartan-derived PPARγ agonists: importance of moiety shift from position 6 to 5 on potency, efficacy and cofactor recruitment.
abstract: 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 AT1-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 EC50 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.
authors.affiliation: Institute of Pharmacology, Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin (Germany).
authors.forename: Lena
authors.initials: L
authors.lastname: Herbst
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bandholtz
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000077333:Telmisartan; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D001572:Benzofurans; D008024:Ligands; D047495:PPAR gamma; D013876:Thiophenes; C088015:benzothiophene; C031000:benzimidazole; C105430:benzofuran; D000077333:Telmisartan
keywords: PPARγ; SPPARMs; cofactors; structure-activity relationships; telmisartan