Elucidating the mechanism of cytochrome p450-mediated pyrimidine ring conversion to pyrazole metabolites with the bace1 inhibitor gne-892 in ratss

Drug Metabolism and Disposition

Volumn 42, Issue 5, 2014, Pages 890-898

  Takahashi, Ryan ^a   Ma, Shuguang ^a   Deese, Alan ^b   Yue, Qin ^a   Kim Kang, Heasook ^d   Yi, Yijun ^d   Siu, Michael ^c   Hunt, Kevin W ^e   Kallan, Nicholas C ^e   Hop, Cornelis E C A ^a   Liu, Xingrong ^a   Khojasteh, S Cyrus ^a  

^a Departments of Pharmacokinetics and Drug Metabolism   (United States)

^b Small Molecule Pharmaceutical Sciences   (United States)

^c Discovery Chemistry   (United States)

^d GENENTECH INC   (United States)

^e ARRAY BIOPHARMA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 AMINOBENZOTRIAZOLE; 2 AMINO 1,3',3' TRIMETHYL 7' (PYRIMIDIN 5 YL) 3',4' DIHYDRO 2'H SPIRO[IMIDAZOLE 4,1' NAPHTHALEN] 5(1H) ONE; CARBON 14; CYTOCHROME P450; DRUG METABOLITE; ENZYME INHIBITOR; FORMIC ACID; GNE 892; PYRAZOLE DERIVATIVE; PYRIMIDINE; PYRIMIDINE 1 OXIDE; PYRIMIDINE DERIVATIVE; RECOMBINANT CYTOCHROME P450 2D2; RECOMBINANT ENZYME; UNCLASSIFIED DRUG; 2-AMINO-1,3',3'-TRIMETHYL-7'-(PYRIMIDIN-5-YL)-3',4'-DIHYDRO-2'H-SPIRO(IMIDAZOLE-4,1'-NAPHTHALEN)-5(1H)-ONE; ASPARTIC PROTEINASE; BACE PROTEIN, RAT; CYP2D2 PROTEIN, RAT; IMIDAZOLE DERIVATIVE; PYRAZOLE; SECRETASE; SPIRO COMPOUND; UNSPECIFIC MONOOXYGENASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG METABOLISM; DRUG STRUCTURE; DRUG TRANSFORMATION; HYDROLYSIS; IN VITRO STUDY; LIVER CELL; LIVER METABOLISM; LIVER MICROSOME; MALE; MASS SPECTROMETRY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; OXIDATION; PRIORITY JOURNAL; RAT; SINGLE DRUG DOSE; ANIMAL; ANTAGONISTS AND INHIBITORS; BILE; BIOTRANSFORMATION; CELL CULTURE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; FECES; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; METABOLISM; SPRAGUE DAWLEY RAT; TANDEM MASS SPECTROMETRY; URINE;

AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ARYL HYDROCARBON HYDROXYLASES; ASPARTIC ACID ENDOPEPTIDASES; BILE; BIOTRANSFORMATION; CELLS, CULTURED; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; ENZYME INHIBITORS; FECES; HEPATOCYTES; IMIDAZOLES; MALE; PYRAZOLES; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; SPIRO COMPOUNDS; TANDEM MASS SPECTROMETRY;

EID: 84898832880     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.114.057141     Document Type: Article

References (14)

1. Ghosal A, Ramanathan R, Yuan Y, Hapangama N, Chowdhury SK, Kishnani NS, and Alton KB (2007) Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. Drug Metab Dispos 35:2186-2195.
2. Groves JT(2005) Models and mechanisms of cytochrome P450 action, in Cytochrome P450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano PR ed) pp 1-43, Plenum Publishers, New York.
3. Hardy JA and Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256:184-185.
4. Hunt KW, Cook AW, Watts RJ, Clark CT, Vigers G, Smith D, Metcalf AT, Gunawardana IW, Burkard M, and Cox AA, et al. (2013) Spirocyclic b-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid b in a higher species. J Med Chem 56:3379-3403.
5. Isobe T, Hichiya H, Hanioka N, Yamamoto S, Shinoda S, Funae Y, Satoh T, Yamano S, and Narimatsu S (2005) Different effects of desipramine on bufuralol 10-hydroxylation by rat and human CYP2D enzymes. Biol Pharm Bull 28:634-640.
6. Lindgren A, Eklund G, Turek D, Malmquist J, Swahn BM, Holenz J, von Berg S, Karlström S, and Bueters T (2013) Biotransformation of two b-secretase inhibitors including ring opening and contraction of a pyrimidine ring. Drug Metab Dispos 41:1134-1147.
7. Liu X, Wong H, Scearce-Levie K, Watts RJ, Coraggio M, Shin YG, Peng K, Wildsmith KR, Atwal JK, and Mango J, et al. (2013) Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing. Drug Metab Dispos 41:1319-1328.
8. Makaji E, Trambitas CS, Shen P, Holloway AC, and Crankshaw DJ (2010) Effects of cytochrome P450 inhibitors on the biotransformation of fluorogenic substrates by adult male rat liver microsomes and cDNA-expressed rat cytochrome P450 isoforms. Toxicol Sci 113:293-304.
9. Penner N, Xu L, and Prakash C (2012) Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how? Chem Res Toxicol 25:513-531.
10. Prakash C and Cui D (1997) Metabolism and excretion of a new antianxiety drug candidate, CP-93,393, in cynomolgus monkeys: identification of the novel pyrimidine ring cleaved metabolites. Drug Metab Dispos 25:1395-1406.
11. Roffey SJ, Obach RS, Gedge JI, and Smith DA (2007) What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 39:17-43.
12. Sharma R, Sun H, Piotrowski DW, Ryder TF, Doran SD, Dai H, and Prakash C (2012) Metabolism, excretion, and pharmacokinetics of ((3,3-difluoropyrrolidin- 1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab Dispos 40:2143-2161.
13. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, and Loeloff R, et al. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-741.
14. Vaz ADN (2003) Dioxygen activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates, in Drug Metabolizing Enzymes: Cytochrome P450 and Other Enzymes in Drug Discovery and Development (Lee JS, Obach RS, Fisher MB, eds) pp 1-32, Marcel Dekker, New York.