Methoxytetrahydropyrans. A new series of selective and orally potent 5- lipoxygenase inhibitors

Article abstract of DOI:10.1021/jm00092a010

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth- 2-ylmethoxy)phenyl]-1-thiazol-2-ylpropyl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2- ylmethoxy)phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C₄ (LTC₄) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB₄ synthesis in A-23187-stimulated human whole blood (IC₅₀s 0.5 nM and 0.07 μM, respectively). In the rat 4f inhibited LTB₄ synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED₅₀ 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4- methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC₅₀s in mouse macrophages and human whole blood of 3 nM and 0.02 μM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 μM in human blood, a selectivity for 5-LPO over CO of >20 000-fold. In the rat 4y inhibited the formation of LTB₄ in blood ex vivo and in inflammatory exudate with ED₅₀s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.