Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats

We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed...

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Veröffentlicht in:	Drug metabolism and disposition 2014-05, Vol.42 (5), p.890-898
Hauptverfasser:	Takahashi, Ryan, Ma, Shuguang, Deese, Alan, Yue, Qin, Kim-Kang, Heasook, Yi, Yijun, Siu, Michael, Hunt, Kevin W, Kallan, Nicholas C, Hop, Cornelis E C A, Liu, Xingrong, Khojasteh, S Cyrus
Format:	Artikel
Sprache:	eng
Schlagworte:	Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aryl Hydrocarbon Hydroxylases - metabolism Aspartic Acid Endopeptidases - antagonists & inhibitors Bile - metabolism Biotransformation Cells, Cultured Chromatography, High Pressure Liquid Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - urine Feces - chemistry Hepatocytes - drug effects Hepatocytes - enzymology Imidazoles - metabolism Imidazoles - pharmacokinetics Imidazoles - urine Male Pyrazoles - metabolism Pyrimidines - metabolism Rats Rats, Sprague-Dawley Spiro Compounds - metabolism Spiro Compounds - pharmacokinetics Spiro Compounds - urine Tandem Mass Spectrometry
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Zusammenfassung:	We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for
ISSN:	0090-9556 1521-009X
DOI:	10.1124/dmd.114.057141