RESUMO
A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.
Assuntos
Amidas/química , Endopeptidases/metabolismo , Inibidores de Proteases/síntese química , Secretases da Proteína Precursora do Amiloide , Sítios de Ligação , Imunoensaio , Peptídeos/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
