Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 57(5): 1753-69, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23672640

RESUMO

HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.


Assuntos
Antivirais/uso terapêutico , Descoberta de Drogas , Lactamas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Ciclopropanos , Cães , Isoindóis , Lactamas/química , Lactamas/farmacologia , Lactamas Macrocíclicas , Macaca fascicularis , Estrutura Molecular , Prolina/análogos & derivados , Inibidores de Proteases/farmacologia , Ratos , Sulfonamidas/química , Sulfonamidas/farmacologia
2.
Biochemistry ; 42(3): 718-27, 2003 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-12534284

RESUMO

Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Vírus da Influenza A/enzimologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Aminas/química , Animais , Sítios de Ligação , Aves , Técnicas de Química Combinatória/métodos , Cristalização , Cristalografia por Raios X , Ciclopentanos/síntese química , Inibidores Enzimáticos/química , Ésteres , Modelos Moleculares , Nanotecnologia/métodos , Neuraminidase/isolamento & purificação , Pirrolidinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade
3.
Org Lett ; 4(7): 1167-70, 2002 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-11922809

RESUMO

[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.


Assuntos
Benzodiazepinas/síntese química , Nitrilas/química , Piperazinas/síntese química , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Espectrometria de Massas , Polímeros , Espectrofotometria Ultravioleta
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...