Identification of two novel metabolites of SCH 486757, a nociceptin/orphanin FQ peptide receptor agonist, in humans

Drug Metabolism and Disposition

Volumn 38, Issue 11, 2010, Pages 2067-2074

  Penner, Natalia A ^a,b   Ho, Ginny ^a   Bercovici, Ana ^a   Chowdhury, Swapan K ^a   Alton, Kevin B ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b BIOGEN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBON 14; DRUG METABOLITE; ENDO 8[BIS(2 CHLOROPHENYL)METHYL] 3 (2 PYRIMIDINYL) 8 AZABICYCLO[3.2.1]OCTAN 3 OL; NOCICEPTIN; NOCICEPTIN RECEPTOR AGONIST; PLACEBO; PYRIDINIUM DERIVATIVE; SCH 486757; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BLOOD SAMPLING; CONTROLLED STUDY; DEUTERIUM HYDROGEN EXCHANGE; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG STRUCTURE; HUMAN; HUMAN EXPERIMENT; LIQUID CHROMATOGRAPHY; MALE; MASS SPECTROMETRY; NONHUMAN; NORMAL HUMAN; PRIORITY JOURNAL; RAT; STANDARD; SUBSTITUTION REACTION; URINALYSIS;

ANIMALS; ANTITUSSIVE AGENTS; AZABICYCLO COMPOUNDS; BIOTRANSFORMATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; HUMANS; MALE; MOLECULAR CONFORMATION; PYRIDINIUM COMPOUNDS; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, OPIOID; TANDEM MASS SPECTROMETRY;

EID: 78049413569     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.110.032516     Document Type: Article

References (17)

1. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, and Vallejo R (2008) Opioid complications and side effects. Pain Physician 11:S105-S120.
2. Chen G, Daaro I, Pramanik BN, and Piwinski JJ (2009) Structural characterization of in vitro rat liver microsomal metabolites of antihistamine desloratadine using LTQ-Orbitrap hybrid mass spectrometer in combination with online hydrogen/deuterium exchange HR-LC/MS. J Mass Spectrom 44:203-213.
3. Chen HX, Chen Y, Du P, and Han FM (2007) LC-MS for identification and elucidation of the structure of in-vivo and in-vitro metabolites of atropine. Chromatographia 65:413-418.
4. de Simone R, Margarucci L, and de Feo V (2008) Tropane alkaloids: an overview. Pharmacologyonline 1:70-89.
5. Dräger B (2002) Analysis of tropane and related alkaloids. J Chromatogr A 978:1-35.
6. Fattorusso E and Taglialatela-Scafati O (2008) Modern Alkaloids: Structure, Isolation, Synthesis and Biology, Wiley VCH Verlag, Weinheim, Germany.
7. Graham-Lorence S, Amarneh B, White RE, Peterson JA, and Simpson ER (1995) A three-dimensional model of aromatase cytochrome P450. Protein Sci 4:1065-1080.
8. He H, McKay G, and Midha KK (1995) Phase I and II metabolites of benztropine in rat urine and bile. Xenobiotica 25:857-872.
9. Ho GD, Anthes J, Bercovici A, Caldwell JP, Cheng KC, Cui X, Fawzi A, Fernandez X, Greenlee WJ, Hey J, et al. (2009) The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety. Bioorg Med Chem Lett 19:2519-2523.
10. Liu DQ and Hop CE (2005) Strategies for characterization of drug metabolites using liquid chromatography-tandem mass spectrometry in conjunction with chemical derivatization and on-line H/D exchange approaches. J Pharm Biomed Anal 37:1-18.
11. Ma S, Chowdhury SK, and Alton KB (2006) Application of mass spectrometry for metabolite identification. Curr Drug Metab 7:503-523.
12. Nassar AE (2003) Online hydrogen-deuterium exchange and a tandem-quadrupole time-of-flight mass spectrometer coupled with liquid chromatography for metabolite identification in drug metabolism. J Chromatogr Sci 41:398-404.
13. Prakash C, Shaffer CL, and Nedderman A (2007) Analytical strategies for identifying drug metabolites. Mass Spectrom Rev 26:340-369.
14. Segall MD, Beresford AP, Gola JM, Hawksley D, and Tarbit MH (2006) Focus on success: using a probabilistic approach to achieve an optimal balance of compound properties in drug discovery. Expert Opin Drug Metab Toxicol 2:325-337. (Pubitemid 46372373)
15. Smith DA and Obach RS (2006) Metabolites and safety: what are the concerns, and how should we address them? Chem Res Toxicol 19:1570-1579.
16. U.S. Department of Health and Human Services (2008) Guidance for Industry: Safety Testing of Drug Metabolites. Food and Drug Administration, Rockville, MD.
17. Varty GB, Lu SX, Morgan CA, Cohen-Williams ME, Hodgson RA, Smith-Torhan A, Zhang H, Fawzi AB, Graziano MP, Ho GD, et al. (2008) The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8- azabicyclo[3.2.1]octan-3-ol (SCH 221510). J Pharmacol Exp Ther 326:672-682.