RESUMO
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Guanidina/farmacologia , Pirróis/química , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Inibidores Enzimáticos/química , Guanidina/química , HumanosRESUMO
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
Assuntos
Secretases da Proteína Precursora do Amiloide/química , Guanidinas/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Domínio Catalítico , Cristalografia por Raios X , Guanidinas/química , Ligação de Hidrogênio , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy. The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described. Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.
Assuntos
Antibacterianos/síntese química , Proteínas de Transporte/química , Proteínas de Ciclo Celular/química , Proteínas de Escherichia coli/química , Indóis/síntese química , Piperidinas/síntese química , Antibacterianos/farmacologia , Divisão Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Escherichia coli/citologia , Escherichia coli/efeitos dos fármacos , Indóis/farmacologia , Concentração Inibidora 50 , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.
