AZOLE PHENOXY HYDROXYUREAS AS SELECTIVE AND ORALLY-ACTIVE INHIBITORS OF 5-LIPOXYGENASE

Azole phenoxy hydroxyureas are a new class of 5-lipoxygenase (5-LO) in hibitors. Structure-activity relationship studies have demonstrated th at electronegative substituents on the 8-phenyl portion of the oxazole tail increased the ex vivo potency of these inhibitors. Similar subst itutions on the thiazole analogs had only minor contribution to the ex vivo activity. The trifluoromethyl-substituted oxazole 24 was the bes t compound of the oxazole series in both the ex vivo (6 h pretreated r ats) and in vivo (3 h pretreated rats) RPAR assay with ED(50) values o f approximately 1 and 3.6 mg/kg, respectively, but was weakly active i n 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. T he unsubstituted thiazole 52 was the best compound of the thiazole ser ies, by inhibiting the leukotriene Bq biosynthesis in the RPAR assay ( 3 h pretreated rats) by 99%, at an oral dose of 10 mg/kg, and the bron choconstriction in the allergic guinea pig by 50%, at an intravenous d ose of 10 mg/kg. Oxatole 24 demonstrated high and selective 5-LO inhib itory activity in the in vitro assays, with IC50 values ranging from 0 .08 mu M in mouse macrophages to 0.8 mu M in human peripheral monocyte s to 1.2 mu M in human whole blood. This activity was selective for 5- LO, as concentrations up to 15 mu M in mouse macrophages did not affec t prostaglandin formation. Oxazole 59 was the most active inhibitor in the human monocyte assay with an IC50 value of 7 nM.