ISOLATION AND IDENTIFICATION OF METABOLITES OF LEUKOTRIENE A(4) HYDROLASE INHIBITOR SC-57461 IN RATS

The metabolic fate of SC-57461, -[3-[4-(phenylmethyl)phenoxy]propyl]-b eta-alanine, a potent and specific inhibitor of the leukotriene A(4) h ydrolase, was determined by LC/MS/MS, NMR and GC/MS in male Sprague-Da wley rats, The major metabolites of SC-57461 in rats were the desmethy l metabolite, the hydroxylated metabolite, the N-oxide metabolite, the hydroxylamine metabolite, and the propionic acid metabolite. The N-ox ide metabolite was found to be stable in the rat plasma and urine, but was unstable in most organic solvents (methanol, acetonitrile, and me thylene chloride, etc.) because of the classic Cope reaction of the N- oxide, which led to the formation of the corresponding hydroxylamine p roduct and acrylic acid. The hydroxylamine metabolite and acrylic acid were reactive in the biomatrix and could not be isolated in the in vi vo samples. However, formation of the hydroxylamine metabolite and acr ylic acid from the N-oxide metabolite in methylene chloride was verifi ed by NMR. The propionic acid metabolite was found to be the common me tabolite shared by SC-57461, N-oxide metabolite, as well as the hydrox ylamine metabolite, which suggested a sequential metabolism of SC-5746 1 in rats. The ultimate fate of the propionic acid metabolite was inco rporation into rat glycerolipid metabolism as a result of its structur al similarity to aryl-substituted propionic acid, a known class of com pounds that can be incorporated into rat glycerolipid metabolism, Fina lly, the isolated hydroxylated metabolite and the N-desmethyl metaboli te were found to have excellent inhibitory effects toward leukotriene A(4) hydrolase and therefore were the major active metabolites of SC-5 7461 in rats.