Naphthalenic lignan lactones as selective, nonredox 5-lipoxygenase inhibitors. Synthesis and biological activity of (methoxyalkyl)thiazole and methoxytetrahydropyran hybrids.
Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg).
Ducharme
Y
Y
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Brideau
C
C
Dubé
D
D
Chan
C C
CC
Falgueyret
J P
JP
Gillard
J W
JW
Guay
J
J
Hutchinson
J H
JH
McFarlane
C S
CS
Riendeau
D
D
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C086166:7-((3-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)methoxy)-4-phenylnaphtho(2,3-c)furan-1(3H)-one; D001572:Benzofurans; D007783:Lactones; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D013844:Thiazoles; D008084:Lipoxygenase