Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
5.
Bioorg Med Chem Lett ; 18(15): 4438-41, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18619839

RESUMO

This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.


Assuntos
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Técnicas de Química Combinatória , Estrutura Molecular , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 18(6): 1910-5, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291644

RESUMO

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.


Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Isoindóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Desenho de Drogas , Humanos , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Nitrilos/farmacologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Ligação Proteica , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Compostos de Tosil/farmacologia , Células Tumorais Cultivadas
7.
Bioorg Med Chem Lett ; 15(2): 271-6, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15603938

RESUMO

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.


Assuntos
Antagonistas de Androgênios/síntese química , Indóis/química , Antagonistas de Androgênios/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Indóis/farmacologia , Isoformas de Proteínas , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Bioorg Med Chem Lett ; 15(2): 389-93, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15603960

RESUMO

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Indóis/química , Animais , Humanos , Concentração Inibidora 50 , Masculino , Mutação , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
J Biol Chem ; 278(34): 32423-30, 2003 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-12782640

RESUMO

Prostate-specific antigen (PSA) is the most valuable marker for the evaluation of prostate cancer progression. The expression of PSA is controlled by androgen receptor (AR) through its binding to androgen-response elements (AREs). Several AREs have been identified within the 5.8-kb PSA promoter. The main activity of this 5.8-kb PSA promoter resides in a 455-bp enhancer core region located about 4 kb upstream of the TATA box. Our study suggests that in addition to the four AREs identified in the PSA enhancer core, another regulatory element (GAGATA), which is located at the region designated PSA3.1, also contributes to transcriptional regulation by androgens. Furthermore, electrophoretic mobility shift assay revealed that a putative transcriptional factor bound the GAGATA sequence in the PSA-producing prostate cancer cell. Further studies demonstrated that GAGATA factor preferentially bound the (G/C)(A/C/T)GATA sequence. The replacement of ATA with GGG in the GAGATA sequence completely eliminated the androgen-mediated transcriptional activity of the enhancer core. By using DNA-coupled magnetic beads and the Southwestern method, a 56-60-kDa protein was identified as the putative GAGATA binding factor. EMSA and Western blotting assay suggested that AR is not involved in androgen-mediated activation through PSA3.1. Therefore, we propose that binding of the GAGATA binding factor and AR to GAGATA and AREs, respectively, of the PSA enhancer core are required for the maximum transcriptional response to androgens.


Assuntos
Androgênios/fisiologia , Regulação da Expressão Gênica/fisiologia , Antígeno Prostático Específico/metabolismo , Fatores de Transcrição/fisiologia , Sequência de Bases , DNA , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Masculino , Dados de Sequência Molecular , Família Multigênica , Antígeno Prostático Específico/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA