Criteria for the identification of non-redox inhibitors of 5-lipoxygenase.
Methoxyalkyl thiazoles have been identified as a novel series of selective 5-lipoxygenase inhibitors with anti-inflammatory properties (Bird et al., J Med Chem 34: 2176-2186, 1991). Based on their structure, it was proposed that the potency of these compounds is not due to redox or iron-chelating properties. In the studies reported here, it was found that the model compounds 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (ICI 211965) and 3-[1-(4-chlorobenzyl)-4-methyl-6-(5- phenylpyridin-2-ylmethoxy)-4,5-dihydro-1H-thiopyrano[2 ,3,4-c,d]indol-2- yl]-2,2-dimethylpropanoic acid (L-689,065) (1) are inactive as reducing substrates in the 5-lipoxygenase-catalyzed decomposition of lipid hydroperoxides, (2) inhibit the 5-lipoxygenase-catalyzed reaction of reducing agents with lipid hydroperoxides, and (3) strongly inhibit the turnover-dependent inactivation of 5-lipoxygenase. These three observations with ICI 211965 and L-689,065 are in contrast to the behavior of other potent 5-lipoxygenase inhibitors from other structural classes, such as L-670,630, BW A4C, and zileuton, which all function as reducing substrates for 5-lipoxygenase. The data indicate that methoxyalkyl thiazoles and thiopyranoindoles are reversible dead-end inhibitors of 5-lipoxygenase and that the effects of inhibitors on the pseudoperoxidase activity and rate of enzyme inactivation provide simple tests to distinguish between redox and non-redox inhibitors of 5-lipoxygenase.
Falgueyret
J P
JP
Department of Biochemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.
Hutchinson
J H
JH
Riendeau
D
D
D001094:Arachidonate 5-Lipoxygenase / Q000302:isolation & purification; D044482:Benzeneacetamides; D001572:Benzofurans / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D015289:Leukotrienes / Q000737:chemistry; D008054:Lipid Peroxides / Q000737:chemistry; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes / Q000737:chemistry; D010084:Oxidation-Reduction; D013844:Thiazoles / Q000737:chemistry
D044482:Benzeneacetamides; D001572:Benzofurans; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D015289:Leukotrienes; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D013844:Thiazoles; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C069794:ICI 211965; C074028:L 670630; C080279:L 689065; C025348:arachidonic acid 5-hydroperoxide; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea