Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor.
A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC50s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtho l (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.
Yatabe
T
T
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kayakiri
H
H
Kawai
Y
Y
Oku
T
T
Tanaka
H
H
D000707:Anaphylaxis / Q000517:prevention & control; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009284:Naphthols / Q000138:chemical synthesis* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009904:Optical Rotation; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013189:SRS-A / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D011804:Quinolines; D013189:SRS-A; C074243:FR 110302; D017997:Leukotriene C4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid