Quinoline-based derivatives of pirinixic acid as dual PPAR alpha/gamma agonists.
Pirinixic acid is known for its peroxisome proliferator-activated receptor (PPAR) agonistic action. In a recent publication, we have shown that aliphatic alpha-substitution of pirinixic acid enhances both PPARalpha and PPARgamma agonism. The goal of this study was to evaluate, whether the PPAR agonism of pirinixic acid may be also maintained in quinoline-based derivatives. The present study revealed that the mere substitution of the dimethyl aniline moiety of pirinixic acid by quinoline leads to a total loss of PPARalpha/gamma agonism, whereas concomitant alpha-substitution with n-butyl or n-hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARalpha/gamma agonists. In the following we report the synthesis of quinoline-based derivatives of pirinixic acid, which in a Gal4-based luciferase-reporter gene assay proved to be potent dual PPARalpha/gamma agonists. Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that of tesaglitazar.
Popescu
Laura
L
Johann Wolfgang Goethe University Frankfurt, Institute of Pharmaceutical Chemistry/ZAFES, Frankfurt, Germany.
Rau
Oliver
O
Böttcher
Jark
J
Syha
Yvonne
Y
Schubert-Zsilavecz
Manfred
M
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; D011804:Quinolines; C006253:pirinixic acid; D008156:Luciferases