RESUMO
The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Pirimidinas/farmacologia , Administração Oral , Animais , Aurora Quinase A , Aurora Quinases , Sítios de Ligação , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/síntese química , Purinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/fisiologia , Piperidinas/farmacologia , Tropanos/farmacologia , Animais , Fármacos Anti-HIV/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Concentração Inibidora 50 , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tropanos/química , Tropanos/farmacocinética , Internalização do Vírus/efeitos dos fármacosRESUMO
A self-assembled, cylindrical capsule was used to bind N-alpha-protected amino acid esters. The reversible encapsulation was studied using NMR spectroscopy in deuterated mesitylene solution and by computer-aided molecular modeling. BOC-L-alanine alkyl esters and BOC-beta-alanine alkyl esters were tested as guests, and the relative binding affinities were established by direct competition experiments. A good correlation was found between the experimental and calculated relative binding affinities in these two series. Guests that were slightly longer than the internal dimensions of the cavity were accommodated by adopting compacted conformations.
