Characterization of new PPARgamma agonists: analysis of telmisartan's structural components.
In addition to a proven efficacy in lowering blood pressure, the AT1 receptor blocker telmisartan has recently been shown to exert pleiotropic effects as a partial agonist of the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Based on these findings and an excellent side-effect profile, telmisartan may serve as a lead structure for the development of new PPARgamma ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPARgamma activation. Synthesized compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV. The data obtained in this structure-activity relationship (SAR) study provide the basis for the development of new PPARgamma ligands, which could lead to active compounds with a distinct, beneficial pharmacological profile compared with the existing full agonists. The basic 1-(biphenyl-4-ylmethyl)-1H-benzimidazole scaffold of telmisartan was identified as an essential moiety with either a carboxylic acid or tetrazole group at the C-2 position of the biphenyl. For maximum potency and activity, the alkyl chain in position 2 requires a minimum length of at least two C atoms (ethyl group), while the methyl group at position 4 of the benzimidazole core seems to contribute to partial activity. An additional benzimidazole at position 6 appears to be a further determinant of potency. Similar conclusions can be drawn for the methyl group in position 1.
Goebel
Matthias
M
Institute of Pharmacy, Freie Universität of Berlin, Koenigin-Luise Strasse 2+4, 14195 Berlin, Germany.
Clemenz
Markus
M
Staels
Bart
B
Unger
Thomas
T
Kintscher
Ulrich
U
Gust
Ronald
R
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000077333:Telmisartan
D001562:Benzimidazoles; D001565:Benzoates; D008024:Ligands; D047495:PPAR gamma; D008156:Luciferases; D000077333:Telmisartan