Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase

• Published in: Agents and actions Vol. 34; no. 1-2; p. 110
• Main Authors: McMillan, R M, Bird, T G, Crawley, G C, Edwards, M P, Girodeau, J M, Kingston, J F, Foster, S J
• Format: Journal Article
• Language: English
• Published: Switzerland 01.09.1991
• Subjects: Animals; Cell Line; Eicosanoids - biosynthesis; Humans; In Vitro Techniques; Leukotrienes - biosynthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Macrophages - drug effects; Macrophages - enzymology; Mice; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0065-4299
• DOI: 10.1007/BF01993252

Methoxyalkyl thiazoles are novel 5-lipoxygenase inhibitors which are neither redox agents nor iron chelators and are exemplified by ICI211965 [1-(3-(naphth-2-ylmethoxy)phenyl)-1-(thiazol-2-yl)prop yl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50 = 0.0085 microM) and its selectivity with respect to cyclo-oxygenase (greater than 5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human blood in vitro (IC50 = 0.45 microM) and rat blood ex vivo (ED50 = 10 mg/Kg, p.o.). Methoxyalkyl thiazoles exhibit a tight structure activity relationship and resolution of a chiral member of the series demonstrates that 5-lipoxygenase inhibition resides largely in one enantiomer. Methoxyalkyl thiazoles represent the first class of agents for which 5-lipoxygenase inhibition is mediated by specific, enantioselective interaction with the enzyme.