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1.
ACS Med Chem Lett ; 13(7): 1165-1171, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35859878

RESUMO

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

2.
Bioorg Med Chem Lett ; 51: 128376, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560263

RESUMO

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Desenvolvimento de Medicamentos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbolinas/administração & dosagem , Carbolinas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Proteínas/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia
3.
Neuropsychopharmacology ; 41(2): 568-77, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26105137

RESUMO

Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.


Assuntos
Cognição/efeitos dos fármacos , Cognição/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Bromo/farmacologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Estudos de Coortes , Combinação de Medicamentos , Glutamatos/farmacologia , Ketamina/farmacologia , Macaca , Magnésio/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Fenetilaminas/farmacologia , Piperidinas/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Piridinas/farmacologia , Tempo de Reação , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , beta-Ciclodextrinas/farmacologia
4.
J Med Chem ; 56(4): 1670-6, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23374053

RESUMO

In vitro studies suggested that the ammonium salt 2 could be a viable prodrug of the HIV-1 attachment inhibitor 1. Increased systemic exposure of the parent drug 1 following oral administration of the amminium salt 2 when compared to similar studies using solution dosing of the parent compound was observed in the in vivo studies in both rats and dogs. At high doses, the improvement in oral exposure of the parent drug was even more evident, indicating that the increased solubility of the amminium salt 2 can overcome dissolution-limited absorption and demonstrating the potential utility of this compound as a prodrug of 1.


Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Piperazinas/síntese química , Pró-Fármacos/síntese química , Piridinas/síntese química , Pirróis/síntese química , Triazinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Antibacterianos/farmacologia , Fármacos Anti-HIV/farmacocinética , Cães , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , HIV-1/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Fígado/metabolismo , Masculino , Piperazinas/farmacocinética , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Piridinas/farmacocinética , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazóis/farmacocinética , Ligação Viral/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 18(18): 5027-31, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18752949

RESUMO

The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzimidazóis/química , Técnicas de Química Combinatória , Cães , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
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