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1.
Bioorg Med Chem Lett ; 22(18): 5995-8, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22902653

RESUMO

A series of aminothiazoles that are potent inhibitors of LIM kinases 1 and 2 is described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin. Consistent with the important role of the LIM kinases in regulating cytoskeletal structure, treated cells displayed dramatically reduced F-actin content.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Quinases Lim/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Quinases Lim/metabolismo , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
2.
Bioorg Med Chem Lett ; 20(5): 1744-8, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20153189
3.
J Med Chem ; 52(9): 3084-92, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19361209

RESUMO

This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/síntese química , Triazinas/farmacologia , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Cães , Concentração Inibidora 50 , Ratos , Solubilidade , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/farmacocinética , Água/química
4.
J Med Chem ; 52(9): 3073-83, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19361210

RESUMO

This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ensaios Clínicos como Assunto , Cães , Feminino , Concentração Inibidora 50 , Masculino , Ratos , Receptores de Amina Biogênica/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Triazinas/farmacocinética , Triazinas/uso terapêutico
5.
Mol Cancer Ther ; 7(11): 3490-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19001433

RESUMO

In developing inhibitors of the LIM kinases, the initial lead molecules combined potent target inhibition with potent cytotoxic activity. However, as subsequent compounds were evaluated, the cytotoxic activity separated from inhibition of LIM kinases. A rapid determination of the cytotoxic mechanism and its molecular target was enabled by integrating data from two robust core technologies. High-content assays and gene expression profiling both indicated an effect on microtubule stability. Although the cytotoxic compounds are still kinase inhibitors, and their structures did not predict tubulin as an obvious target, these results provided the impetus to test their effects on microtubule polymerization directly. Unexpectedly, we confirmed tubulin itself as a molecular target of the cytotoxic kinase inhibitor compounds. This general approach to mechanism of action questions could be extended to larger data sets of quantified phenotypic and gene expression data.


Assuntos
Antineoplásicos/química , Antineoplásicos/toxicidade , Quinases Lim/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Humanos , Quinases Lim/metabolismo , Microscopia de Fluorescência , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas
6.
Psychopharmacology (Berl) ; 165(1): 86-92, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12474122

RESUMO

RATIONALE: CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines. OBJECTIVES: The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP). METHODS: DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined. RESULTS: DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency. CONCLUSIONS: These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.


Assuntos
Ansiolíticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/farmacologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Animais , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ataxia/etiologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Clordiazepóxido/farmacologia , Sedação Consciente , Hormônio Liberador da Corticotropina/análogos & derivados , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Pirazóis/química , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Estresse Fisiológico/metabolismo , Triazinas/química , Triazinas/uso terapêutico
7.
Neuropsychopharmacology ; 26(5): 574-82, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11927182

RESUMO

We examined whether blockade of corticotropin-releasing factor (CRF) receptors by a non-peptide CRF antagonist (DMP696) would attenuate the stress hyper-responsiveness that occurs in response to maternal separation. In a social interaction test as well as the elevated plus maze, adult male rats, which had been maternally separated as infants, displayed more anxiety-like behavior compared with handled rats. DMP696 increased social interaction in both groups. In the elevated plus maze however, DMP696 significantly increased open arm time in the maternally separated rats but not in the handled group whereas chlordiazepoxide increased open arm time in both groups. DMP696 also appeared to block stress-induced ACTH secretion more readily in the maternally separated group compared with the handled rats. These observations suggest that CRF antagonists are particularly effective in animals that are hyper-responsive to stress and may therefore have utility in the treatment of anxiety and affective disorders where CRF has been implicated.


Assuntos
Hormônio Adrenocorticotrópico/sangue , Comportamento Animal/efeitos dos fármacos , Privação Materna , Pirazóis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Ansiolíticos/farmacologia , Comportamento Animal/fisiologia , Clordiazepóxido/farmacologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Gravidez , Ratos , Ratos Long-Evans , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Estresse Psicológico/sangue
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