RESUMO
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Assuntos
Aminas/química , Carbamatos/química , Inibidores Enzimáticos/química , Piperidinas/química , Renina/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/síntese química , Carbamatos/farmacocinética , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos , Ratos Transgênicos , Renina/sangue , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Assuntos
Anti-Hipertensivos/química , Metilaminas/química , Renina/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Pressão Sanguínea , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Metilaminas/síntese química , Metilaminas/farmacocinética , Ratos , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
As the global threat of drug- and antibiotic-resistant bacteria continues to rise, new strategies are required to advance the drug discovery process. This work describes the construction of an array of Escherichia coli strains for use in whole-cell screens to identify new antimicrobial compounds. We used the recombination systems from bacteriophages lambda and P1 to engineer each strain in the array for low-level expression of a single, essential gene product, thus making each strain hypersusceptible to specific inhibitors of that gene target. Screening of nine strains from the array in parallel against a large chemical library permitted identification of new inhibitors of bacterial growth. As an example of the target specificity of the approach, compounds identified in the whole-cell screen for MurA inhibitors were also found to block the biochemical function of the target when tested in vitro.
