Pirinixic acid derivatives as novel dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.
Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.
Koeberle
Andreas
A
Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
Zettl
Heiko
H
Greiner
Christine
C
Wurglics
Mario
M
Schubert-Zsilavecz
Manfred
M
Werz
Oliver
O
D045744:Cell Line, Tumor; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors; D008956:Models, Chemical; D000071876:Prostaglandin-E Synthases; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines; C006253:pirinixic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases