BENZOXAZOLAMINES AND BENZOTHIAZOLAMINES - POTENT, ENANTIOSELECTIVE INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS WITH A NOVEL MECHANISM OF ACTION

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 LTB(4 ) release in human polymorphonuclear leukocytes (IC50 0.23 mu M). Thro ugh structural modification, it was determined that hydrophobic substi tuents in the 5-position and replacement of the phenyl ring of phenyla lanine with a cyclohexyl group greatly enhance potency. Several ester bioisosteres that retain potency and enantiomeric selectivity are desc ribed. Lead optimization culminated in l-1-(2-pyridinyl)ethyl]-5-methy l-2-benzoxazolamine (43b), IC50 0.001 mu M. The compounds described ar e not inhibitors of 5-lipoxygenase but, rather, act at the level of ar achidonic acid release.