Patent Evaluation: Highly potent 5-lipoxygenase inhibitors containing a tetrahydropyranyl moiety

Summary

Novelty: Bicyclic pyrans are disclosed as inhibitors of 5-lipoxygenase and are therefore potentially useful in treating leukotriene-mediated diseases such as asthma.

Biology: Seven standard test models are outlined with activity ranges defined for the compounds. IC₅₀ values against cyclooxygenase are 20–1000 μM (cf. 1 nM-1 μM against LTC₄ synthesis, in the same cells). Specific data are provided for 4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)phenyl]-4-methoxytetrahydropyran, which has an IC₅₀ value of 50 nM against A23187-induced LTB₄ synthesis in human whole blood, and an ED₅₀ < 2 mg/kg po in a zymosan-induced LTB₄ synthesis, in a rat air pouch model.

Chemistry: The compounds are synthesized using conventional methods.

Structure: