title: Identification of two novel metabolites of SCH 486757, a nociceptin/orphanin FQ peptide receptor agonist, in humans.
abstract: The study of human metabolism of endo-8[bis(2-chlorophenyl)methyl]-3-(2-pyrimidinyl)-8-azabicyclo[3.2.1]octan-3-ol (SCH 486757) after a 200-mg oral dose of the drug to healthy volunteers in the first-in-human study is presented. The structural elucidation of two unique metabolites, which were detected in the process of metabolite characterization in human plasma and urine by liquid chromatography-mass spectrometry (LC-MS), is described. These metabolites (M27 and M34) were initially detected in human plasma at high levels (>35% of the LC-MS response of the parent drug). Additional LC-MS experiments (hydrogen/deuterium exchange and accurate mass measurement) were used to determine structures of metabolites. It was found that both metabolites were formed through a loss of the C-C bridge from the tropane moiety with the conversion into a substituted pyridinium compound. This metabolic process has not been reported previously. Because of the apparent high abundance of metabolites based on the LC-MS response, actual circulating amounts of these metabolites relative to the parent drug were determined semiquantitatively to evaluate their coverage in preclinical species. With the use of reference standards, it was shown that the LC-MS response of M27 and M34 in human plasma was much higher than that of the parent compound. Actual amounts of M27 and M34 metabolites were less than 5% of the level of the parent drug; therefore, additional assessment was not required.
authors.affiliation: Departments, Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Penner
authors.forename: Ginny
authors.initials: G
authors.lastname: Ho
authors.forename: Ana
authors.initials: A
authors.lastname: Bercovici
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D053961:Azabicyclo Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D011726:Pyridinium Compounds / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D053719:Tandem Mass Spectrometry; D000094942:Nociceptin Receptor
chemical_list: C549545:8-(bis(2-chlorophenyl)methyl)-3-(2-pyrimidinyl)-8-azabicyclo(3.2.1)octan-3-ol; D000996:Antitussive Agents; D053961:Azabicyclo Compounds; D011726:Pyridinium Compounds; D011743:Pyrimidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor