RT Journal Article
SR Electronic
T1 Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 890
OP 898
DO 10.1124/dmd.114.057141
VO 42
IS 5
A1 Ryan Takahashi
A1 Shuguang Ma
A1 Alan Deese
A1 Qin Yue
A1 Heasook Kim-Kang
A1 Yijun Yi
A1 Michael Siu
A1 Kevin W. Hunt
A1 Nicholas C. Kallan
A1 Cornelis E.C.A. Hop
A1 Xingrong Liu
A1 S. Cyrus Khojasteh
YR 2014
UL http://dmd.aspetjournals.org/content/42/5/890.abstract
AB 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 14C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.