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.
Footnotes
- Abbreviations used are::
- LC
- liquid chromatography
- MS
- mass spectometry
- MS/MS
- tandem mass spectometry
- HPLC
- high performance liquid chromatography
- NMR
- nuclear magnetic resonance
- compound A
- [3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane
- COSY
- correlation spectroscopy
- Received March 21, 2002.
- Accepted May 10, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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