Benzoxazolamines and Benzothiazolamines: Potent, Enantioselective Inhibitors of Leukotriene Biosynthesis with a Novel Mechanism of Action

Article abstract of DOI:10.1021/jm00033a008

A series of benzoxazolamine and benzothiazolamine analogs that inhibit leukotriene (LT) biosynthesis are described.The initial lead, (S)-N-(benzothiazol-2-yl)phenylalanine ethyl ester (5a), was discovered in a screening program for inhibition of Ca-ionophore-A23187-induced LTB₄ release in human polymorphonuclear leukocytes (IC50 0.23 μM).Through structural modification, it was determined that hydrophobic substituents in the 5-position and replacement of the phenyl ring of phenylalanine with a cyclohexyl group greatly enhance potency.Several ester bioisosteres that retain potency and enantiomeric selectivity are described.Lead optimization culminated in (S)-N-<2-cyclohexyl-1-(2-pyridinyl)ethyl>-5-methyl-2-benzoxazolamine (43b), IC50 0.001 μM.The compounds described are not inhibitors of 5-lipoxygenase but, rather, act at the level of arachidonic acid release.