Isolation and identification of metabolites of leukotriene A4 hydrolase inhibitor SC-57461 in rats.
The metabolic fate of SC-57461, N-methyl-N-[3-[4-(phenylmethyl)-phenoxy]propyl]-beta-alanine, a potent and specific inhibitor of the leukotriene A4 hydrolase, was determined by LC/MS/MS, NMR and GC/MS in male Sprague-Dawley rats. The major metabolites of SC-57461 in rats were the desmethyl metabolite, the hydroxylated metabolite, the N-oxide metabolite, the hydroxylamine metabolite, and the propionic acid metabolite. The N-oxide metabolite was found to be stable in the rat plasma and urine, but was unstable in most organic solvents (methanol, acetonitrile, and methylene chloride, etc.) because of the classic Cope reaction of the N-oxide, which led to the formation of the corresponding hydroxylamine product and acrylic acid. The hydroxylamine metabolite and acrylic acid were reactive in the biomatrix and could not be isolated in the in vivo samples. However, formation of the hydroxylamine metabolite and acrylic acid from the N-oxide metabolite in methylene chloride was verified by NMR. The propionic acid metabolite was found to be the common metabolite shared by SC-57461, N-oxide metabolite, as well as the hydroxylamine metabolite, which suggested a sequential metabolism of SC-57461 in rats. The ultimate fate of the propionic acid metabolite was incorporation into rat glycerolipid metabolism as a result of its structural similarity to aryl-substituted propionic acid, a known class of compounds that can be incorporated into rat glycerolipid metabolism. Finally, the isolated hydroxylated metabolite and the N-desmethyl metabolite were found to have excellent inhibitory effects toward leukotriene A4 hydrolase and therefore were the major active metabolites of SC-57461 in rats.
Yuan
J H
JH
G. D. Searle, Skokie, IL 60077, USA.
Birkmeier
J
J
Yang
D C
DC
Hribar
J D
JD
Liu
N
N
Bible
R
R
Hajdu
E
E
Rock
M
M
Schoenhard
G
G
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007262:Infusions, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism
D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; C104311:SC 57461; D015091:beta-Alanine; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase