Patent Evaluation: Hydroxamate/hydroxyurea 5-lipoxygenase inhibitors

Summary

Novelty: Cyclobutyl derivatives are claimed as leukotriene biosynthesis inhibitors. They are potentially useful for the treatment of allergic and inflammatory disease states and also cardiovascular and central nervous system disorders resulting from the formation of leukotrienes following stroke or subarachnoid haemorrhage.

Biology: Inhibition of leukotriene biosynthesis was evaluated in vitro using calcium ionophore-induced LTB₄ biosynthesis. The specified compound gave an IC₅₀ value of 0.13 × 10-⁶M. In vivo leukotriene biosynthesis inhibition was measured using a rat peritoneal anaphylaxis model in a method similar to that of Young et al. (Fed. Am. Soc. Exp. Biol. (1985) 44:1185). The specified compound inhibited leukotriene biosynthesis by 76% at 30 μM/kg.

Chemistry: Preparation is exemplified by one hundred and five compounds. Six compounds are specifically claimed including N-[3-(3-(4-fluorophenoxy)phenyl)cyclobutyl]-N-hydrox-yurea.