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Quinoline‐Based Derivatives of Pirinixic Acid as Dual PPAR α/γ Agonists
Author(s) -
Popescu Laura,
Rau Oliver,
Böttcher Jark,
Syha Yvonne,
SchubertZsilavecz Manfred
Publication year - 2007
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200700042
Subject(s) - quinoline , chemistry , moiety , peroxisome proliferator activated receptor , stereochemistry , peroxisome , docking (animal) , agonist , receptor , aniline , biochemistry , pharmacology , biology , organic chemistry , medicine , nursing
Pirinixic acid is known for its peroxisome proliferator‐activated receptor (PPAR) agonistic action. In a recent publication, we have shown that aliphatic α‐substitution of pirinixic acid enhances both PPARα and PPARγ 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 PPARα/γ agonism, whereas concomitant α‐substitution with n ‐butyl or n ‐hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARα/γ 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 PPARα/γ agonists. Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that of tesaglitazar.