Alpha-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma.
Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARalpha subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARgamma subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARalpha and PPARgamma seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPARalpha/gamma agonist, we improved potency at the human PPARalpha and PPARgamma by substituting the alpha-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPARalpha and 18 for PPARgamma, respectively.
Rau
Oliver
O
Institute of Pharmaceutical Chemistry/ZAFES, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany.
Syha
Yvonne
Y
Zettl
Heiko
H
Kock
Michael
M
Bock
Andreas
A
Schubert-Zsilavecz
Manfred
M
D006801:Humans; D066298:In Vitro Techniques; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D020025:Peroxisome Proliferators / Q000138:chemical synthesis / Q000494:pharmacology*; D000077205:Pioglitazone; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology
D047493:PPAR alpha; D047495:PPAR gamma; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D045162:Thiazolidinediones; C006253:pirinixic acid; D008156:Luciferases; D000077205:Pioglitazone