Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 64(14): 10445-10468, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34255509

RESUMO

A new class of selective vasopressin receptor 1A (V1A) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the in vitro pharmacological profiles of the compounds, the human V1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Benzazepinas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/química , Benzazepinas/síntese química , Benzazepinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Receptores de Vasopressinas , Estereoisomerismo , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 30(18): 127416, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32736211

RESUMO

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Starting from a moderately potent HTS hit (7), we identified a molecule (49) having nanomolar binding strength and functional activity, which is in the same range as the potency of clinically tested V1a antagonists.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Receptores de Vasopressinas/metabolismo , Transtornos do Comportamento Social/tratamento farmacológico , Ureia/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Piperazina/química , Ligação Proteica , Piridinas/química , Quinolinas/química , Relação Estrutura-Atividade , Ureia/farmacologia
3.
Bioorg Med Chem Lett ; 30(18): 127417, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32731087

RESUMO

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Continuing our previous work, we found an in vitro and in vivo orally active V1a selective antagonist molecule (40) among [1,2,4]triazolo[4,3-a][1]benzazepines.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Benzazepinas/síntese química , Receptores de Vasopressinas/metabolismo , Transtornos do Comportamento Social/tratamento farmacológico , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Benzazepinas/farmacologia , Humanos , Concentração Inibidora 50 , Isomerismo , Camundongos , Microssomos Hepáticos/metabolismo , Ligação Proteica , Quinolonas/química , Ratos , Relação Estrutura-Atividade
4.
J Med Chem ; 63(4): 1511-1525, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31951127

RESUMO

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Vasopressinas/metabolismo , Triazóis/uso terapêutico , Adolescente , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Transtorno do Espectro Autista/metabolismo , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Encéfalo/metabolismo , Criança , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Masculino , Mamíferos , Piridinas/síntese química , Piridinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
5.
Br J Pharmacol ; 176(9): 1315-1327, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801659

RESUMO

BACKGROUND AND PURPOSE: We investigated the inhibitory effect and associated molecular mechanisms of tolvaptan on angiotensin II (AngII)-induced aldosterone production in vitro and in vivo. EXPERIMENTAL APPROACH: In vitro, H295R human adrenocarcinoma cells were incubated with 1 µmol·L-1 arginine vasopressin (AVP) or dDAVP, or tolvaptan (0.1, 1, and 3 µmol·L-1 ) in the presence and absence of 100 nmol·L-1 of AngII. In vivo, Sprague-Dawley rats were treated with tolvaptan 0.05% in the diet for 6 days in the presence and absence of 200 pmol·min-1 AngII. KEY RESULTS: Tolvaptan suppressed AngII-induced aldosterone production in a dose-dependent manner in H295R cells, whereas neither AVP nor dDAVP in the presence or absence of AngII altered aldosterone production, suggesting the vasopressin V2 receptor was not involved in the inhibitory effect of tolvaptan on aldosterone synthesis. In addition, tolvaptan inhibited the AngII-induced increase in aldosterone synthase (CYP11B2) protein levels without suppressing CYP11B2 mRNA expression. Notably, tolvaptan increased the levels of unfolded protein response (UPR) marker DDIT3 and eIF2α phosphorylation (a UPR-induced event), which could block the translation of CYP11B2 mRNA into protein and thereby inhibit aldosterone production. In vivo, tolvaptan significantly inhibited AngII-induced increases in serum and adrenal aldosterone levels and CYP11B2 protein levels. This anti-aldosterone effect was associated with a reduction in the elevated systolic and diastolic BP. CONCLUSIONS AND IMPLICATIONS: Tolvaptan inhibited AngII-stimulated aldosterone production via a V2 receptor-independent pathway, which can counteract or even surpass its potential activating effect of diuresis-induced aldosterone secretion in certain aldosterone-mediated pathological conditions.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Receptores de Vasopressinas/metabolismo , Tolvaptan/farmacologia , Glândulas Suprarrenais/química , Aldosterona/síntese química , Aldosterona/química , Aldosterona/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/química , Humanos , Tolvaptan/síntese química , Tolvaptan/química , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA