Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid.
A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of pirinixic acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, compound 1) is presented. Systematic profiling of 1, i.e., esterification of the carboxylic acid, alpha-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 microM). These derivatives may possess potential for intervention with inflammatory and allergic diseases.
Werz
Oliver
O
Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany. oliver.werz@uni-tuebingen.de
Greiner
Christine
C
Koeberle
Andreas
A
Hoernig
Christina
C
George
Sven
S
Popescu
Laura
L
Syha
Ivonne
I
Schubert-Zsilavecz
Manfred
M
Steinhilber
Dieter
D
D000634:Aminoquinolines; D002478:Cells, Cultured; D004951:Esterification; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D007962:Leukocytes / Q000201:enzymology; D008084:Lipoxygenase / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines; C006253:pirinixic acid; D008084:Lipoxygenase