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








Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 55(16): 7061-79, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22891645

RESUMO

The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC(50) = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1ß/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Cartilagem Articular/efeitos dos fármacos , Bases de Dados de Compostos Químicos , Osteoartrite/patologia , Sulfonamidas/síntese química , Triazinas/síntese química , Proteína ADAMTS5 , Agrecanas/metabolismo , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Endopeptidases/metabolismo , Epitopos , Glicosaminoglicanos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Triazinas/farmacocinética , Triazinas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA