Vol. 30, Issue 8, 937-943, August 2002

Identification of Metabolites of a Substance P (Neurokinin 1 Receptor) Antagonist in Rat Hepatocytes and Rat Plasma

Cornelis E. C. A. Hop, Yanfeng Wang, Sanjeev Kumar, Maria Victoria Silva Elipe, Conrad E. Raab, Dennis C. Dean, Grace K. Poon, Carol-Ann Keohane, John Strauss, Shuet-Hing L. Chiu, Neil Curtis, Jason Elliott, Ute Gerhard, Karen Locker, Denise Morrison, Russell Mortishire-Smith, Steven Thomas, Alan P. Watt, and David C. Evans

Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey (C.E.C.A.H., Y.W., S.K., M.V.S.E., C.E.R., D.C.D., G.K.P., C.-A.K., J.S., S.-H.L.C.); and Department of Medicinal Chemistry, Merck Sharp & Dohme, the Neuroscience Research Centre, Terlings Park, United Kingdom (N.C., J.E., U.G., K.L., D.M., R.M.-S., S.T., A.P.W., D.C.E.)

[3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)- 6-phenyl- 1-oxa-7-azaspiro[4.5]decane is a substance P (Neurokinin 1 receptor) antagonist. Substance P antagonists are proven in concept to have excellent potential for the treatment of major depression, and they allow superior and sustained protection from acute and delayed chemotherapy-induced emesis. The metabolism of this compound was investigated in rat hepatocytes, and circulating rat plasma metabolites were identified following oral and intravenous dosing. The turnover in rat hepatocytes within 4 h was about 30%, and the major metabolites were identified as two nitrones and a lactam associated with the piperidine ring. Although these metabolites were also observed in rat plasma, the major circulating metabolite was a keto acid following oxidative de-amination of the piperidine ring. Liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance were used to confirm the structure of the latter metabolite. A mechanism leading to the formation of the keto acid metabolite has been suggested, and most intermediates were observed in rat plasma.