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, inhibito...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-02, Vol.37 (4), p.512-518
Main Authors: Ducharme, Yves, Brideau, Christine, Dube, Daniel, Chan, Chi Chung, Falgueyret, Jean Pierre, Gillard, John W, Guay, Jocelyne, Hutchinson, John H, McFarlane, Cyryl S
Format: Article
Language:English
Subjects:
Animals
Benzofurans - chemical synthesis
Benzofurans - chemistry
Benzofurans - pharmacology
Chemistry
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Lipoxygenase - metabolism
Lipoxygenase Inhibitors - chemical synthesis
Lipoxygenase Inhibitors - chemistry
Lipoxygenase Inhibitors - pharmacology
Male
Naphthalenes - chemical synthesis
Naphthalenes - chemistry
Naphthalenes - pharmacology
Neutrophils - drug effects
Neutrophils - enzymology
Organic chemistry
Preparations and properties
Pyrans - chemical synthesis
Pyrans - chemistry
Pyrans - pharmacology
Rats
Rats, Sprague-Dawley
Saimiri
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00030a010