Identification of metabolites of a substance P (Neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma

Hop, C.E.C.A.; Wang, Y.; Kumar, S.; Elipe, M.V.S.; Raab, C.E.; Dean, D.C.; Poon, G.K.; Keohane, C.-A.; Strauss, J.; Chiu, S.-H.L.; Curtis, N.; Elliott, J.; Gerhard, U.; Locker, K.; Morrison, D.; Mortishire-Smith, R.; Thomas, S.; Watt, A.P.; Evans, D.C.

Author

Hop, C.E.C.A.

Wang, Y.

Kumar, S.

Elipe, M.V.S.

Raab, C.E.

Dean, D.C.

Poon, G.K.

Keohane, C.-A.

Strauss, J.

Chiu, S.-H.L.

Curtis, N.

Elliott, J.

Gerhard, U.

Locker, K.

Morrison, D.

Mortishire-Smith, R.

Thomas, S.

Watt, A.P.

Evans, D.C.

Abstract

[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.