Azole Phenoxy Hydroxyureas as Selective and Orally Active Inhibitors of 5-Lipoxygenase

Abstract

Azole phenoxy hydroxyureas are a new class of 5-lipoxygenase (5-LO) inhibitors. Structure−activity relationship studies have demonstrated that electronegative substituents on the 2-phenyl portion of the oxazole tail increased the ex vivo potency of these inhibitors. Similar substitutions on the thiazole analogs had only minor contribution to the ex vivo activity. The trifluoromethyl-substituted oxazole 24 was the best compound of the oxazole series in both the ex vivo (6 h pretreated rats) and in vivo (3 h pretreated rats) RPAR assay with ED₅₀ values of approximately 1 and 3.6 mg/kg, respectively, but was weakly active in the allergic guinea pig assay. Oxazole 50 was equally active in both the RPAR and guinea pig in vivo models and was similar to zileuton. The unsubstituted thiazole 52 was the best compound of the thiazole series, by inhibiting the leukotriene B₄ biosynthesis in the RPAR assay (3 h pretreated rats) by 99%, at an oral dose of 10 mg/kg, and the bronchoconstriction in the allergic guinea pig by 50%, at an intravenous dose of 10 mg/kg. Oxazole 24 demonstrated high and selective 5-LO inhibitory activity in the in vitro assays, with IC₅₀ values ranging from 0.08 μM in mouse macrophages to 0.8 μM in human peripheral monocytes to 1.2 μM in human whole blood. This activity was selective for 5-LO, as concentrations up to 15 μM in mouse macrophages did not affect prostaglandin formation. Oxazole 59 was the most active inhibitor in the human monocyte assay with an IC₅₀ value of 7 nM.