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1.
Drug Metab Dispos ; 43(3): 358-66, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25547868

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.


Subject(s)
Ions/chemistry , Microsomes, Liver/metabolism , Thiazoles/chemistry , Thiazoles/metabolism , Animals , Chromatography, Liquid/methods , Dogs , Haplorhini , Humans , Macaca fascicularis , Male , Mass Spectrometry/methods , Pyridines/chemistry , Pyridines/metabolism , Rats , Rats, Sprague-Dawley
2.
J Labelled Comp Radiopharm ; 57(5): 342-9, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24700683

ABSTRACT

In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms. Compound 1 was prepared in C-14 labeled form by lithiation of [2,6-(14)C2]2-chloropyridine and subsequent coupling with spirooxirane-2,3'-quinuclidine. When this same coupling was attempted using [3,4,5,6-(2)H4]2-chloropyridine, alcohol [(2)H6]-6 was the major product indicating that the primary isotope effect for the lithiation step was significant enough to shift the reaction pathway. Therefore, an alternate site of labeling was used to prepare [(2)H4]-1. [(13)C5]-2 was prepared in five steps from [(13)C5 ]2-furoic acid, but the C-14 labeled compound used [(14)C2]-1 as the starting material instead. [(14)C2]-3 was prepared in two steps from [carbonyl-(14)C]nicotinic acid.


Subject(s)
Carbon Isotopes/chemistry , Carbon Isotopes/isolation & purification , Niacin/analogs & derivatives , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors , Isotope Labeling , Radiopharmaceuticals/chemical synthesis
3.
Bioorg Med Chem Lett ; 23(2): 543-7, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23237836

ABSTRACT

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.


Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Receptors, Dopamine D2/agonists , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Benzazepines/chemistry , Biological Assay , Disease Models, Animal , Dopamine Agonists/chemistry , Drug Partial Agonism , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Rats , Structure-Activity Relationship
4.
ACS Med Chem Lett ; 4(1): 46-51, 2013 Jan 10.
Article in English | MEDLINE | ID: mdl-24900562

ABSTRACT

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.

5.
J Med Chem ; 50(13): 3113-31, 2007 Jun 28.
Article in English | MEDLINE | ID: mdl-17542571

ABSTRACT

A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.


Subject(s)
Analgesics/chemical synthesis , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Pyridazines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Glycine/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Administration, Oral , Alkynes/chemical synthesis , Alkynes/chemistry , Alkynes/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Brain/metabolism , Chronic Disease , Constriction, Pathologic/complications , Male , Pain/etiology , Peripheral Nervous System Diseases/etiology , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathology , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 13(20): 3553-6, 2003 Oct 20.
Article in English | MEDLINE | ID: mdl-14505669

ABSTRACT

Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.


Subject(s)
Glycine/chemistry , Pyridazines/chemical synthesis , Quinolines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Pyridazines/chemistry , Pyridazines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, N-Methyl-D-Aspartate/chemistry
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