Zhang, M, Eismin, R, Kenttamaa, H, Xiong, H, Wu, Y, Burdette, D and Urbanek, R (2015) Identification of 2-aminothiazolobenzazepine metabolites in human, rat, dog, and monkey microsomes by ion-molecule reactions in linear quadrupole ion trap mass spectrometry. Drug Metabolism and Disposition. pp. 358-366.

Abstract

2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3 ]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation

Item Type:	Article
Additional Information:	NIBR author: Burdette, D institute: NIBR contributor address: Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.) minli.zhang@astrazeneca.comDrug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
Date Deposited:	13 Oct 2015 13:11
Last Modified:	13 Oct 2015 13:11
URI:	https://oak.novartis.com/id/eprint/24931