Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 21(22): 6888-94, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21986586

RESUMO

We have identified and synthesized a series of imidazole containing dimerization inhibitors of inducible nitric oxide synthase (iNOS). The necessity of key imidazole and piperonyl functionality was demonstrated and SAR studies led to the identification of compound 35, which showed a dose dependant inhibition in multiple pain models, including tactile allodynia induced by spinal nerve ligation (Chung model).


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Imidazóis/química , Imidazóis/uso terapêutico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Dor/tratamento farmacológico , Multimerização Proteica/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Endogâmicos Lew
3.
Artigo em Inglês | MEDLINE | ID: mdl-18066870

RESUMO

ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.


Assuntos
Desenho de Fármacos , Guanosina/análogos & derivados , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pirimidinonas/administração & dosagem , Pirimidinonas/síntese química , Receptor 7 Toll-Like/agonistas , Administração Oral , Antivirais/farmacologia , Guanosina/farmacologia , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinética
4.
Cancer Res ; 72(6): 1494-503, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22266222

RESUMO

Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/uso terapêutico , Antagonistas de Androgênios/farmacocinética , Anilidas/farmacocinética , Anilidas/uso terapêutico , Animais , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , Benzamidas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/sangue , Feniltioidantoína/farmacocinética , Feniltioidantoína/uso terapêutico , Ratos , Receptores Androgênicos/efeitos dos fármacos , Tioidantoínas/sangue , Tioidantoínas/síntese química , Tioidantoínas/farmacocinética , Compostos de Tosil/farmacocinética , Compostos de Tosil/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA