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1.
Bioorg Med Chem Lett ; 25(2): 367-71, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25466710

RESUMO

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.


Assuntos
Flúor/química , Flúor/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade
2.
J Med Chem ; 58(1): 512-6, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-24712864

RESUMO

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Isoquinolinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo
3.
J Med Chem ; 54(7): 2255-65, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21375264
4.
Bioorg Med Chem Lett ; 13(23): 4241-4, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14623009

RESUMO

Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.


Assuntos
Anti-Infecciosos/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Diaminas/farmacocinética , Plasma/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Diaminas/administração & dosagem , Diaminas/farmacologia , Infusões Intravenosas , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Ofloxacino/metabolismo , Ofloxacino/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
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