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

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)propyl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50=0.0085 μM) and its selectivity with respect to cyclo-oxygenase (>5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human bloodin vitro (IC50=0.45 μM) and rat bloodex 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.