The leukotrienes (LT) are a group of highly potent lipid mediators that play critical roles in numerous diseases, including inflammatory diseases and allergic disease states (Samuelsson, B., 1983, Leukotrienes: Science 220, 568-575). The enzyme 5-lipoxygenase (5-LO) converts arachidonic acid into the leukotriene A4 (LTA4) which may then be hydrolyzed into leukotriene B4 (LTB4) by the enzyme LTA4 hydrolase, or may react to form leukotriene C4 (LTC4) by a catalytic reaction mediated by LTC4 synthase.
Leukotrienes B4, C4, D4, and E4 have been shown experimentally to play a role in the inflammation involved in asthma. In addition, inhaled LTC4 and leukotriene D4 (LTD4) have been reported to be the most potent bronchoconstrictors yet studied in human subjects. LTC4 and LTD4 have also been reported to possibly cause migration of inflammatory cells into asthmatic airways (O'Byrne, Chest, Vol 111, (2):27).
Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of a number of proinflammatory leukotriene lipid mediators. The critical role of leukotrienes in allergic and respiratory diseases has been demonstrated using several animal models of LT deficiency, particularly 5-LO knock-out mice (Leuchron Contract No. QLG1-CT-2001-01521, Review, The Leukotrienes: Signaling Molecules in Chronic and Degenerative Diseases: Byrum, R. S., Goulet, J. L., Snouwaert, J. N., Griffiths, R. J. & Koller, B. H. (1999), J Immunol 163, 6810-6819. Bailie, M. B., Standiford, T. J., Laichalk, L. L., Coffey, M. J., Strieter, R. & Peters-Golden, M. (1996), J. Immunol. 157, 5221-5224). In addition, drugs that interfere with the biosynthesis and action of LTs have been marketed as novel medications against asthma and allergic rhinitis (Drazen, J. F., Israel, E. & O'Byrne, P. (1999), N. Engl. J. Med. 340, 197-206). For a review article on lipoxygenase inhibitors, see H. Masamune and L. S. Melvin, Sr.: Annual Reports in Medicinal Chemistry, 1989, 24, pp 71-80 (Adademic).
In particular, 4-(3-(4-(2-methyl-1H-imidazol-1-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide was previously tested in human clinical trials (U.S. Pat. No. 5,883,106 and EP 0787127).
There is a need to provide new 5-LO inhibitors that are good drug candidates. Such 5-LO inhibitors should show good potency, possess high levels of selectivity, and have properties particularly suitable for providing effective treatment while minimizing or eliminating side-effects.