RESUMO
Judicious combination of P-region sequences of highly potent anticoagulant proteins including NAP5, NAP6, Ecotin, and Antistasin with SAR from small molecule FXa inhibitors led to a series of chimeric inhibitors of formula 1a-j. We report herein the design, synthesis, and biological activity of this novel family of FXa inhibitors that express both high in vitro potency and superb selectivity against related serine proteases.
Assuntos
Antifibrinolíticos/síntese química , Proteínas de Escherichia coli , Inibidores do Fator Xa , Proteínas Periplásmicas , Inibidores de Serina Proteinase/síntese química , Antifibrinolíticos/química , Antifibrinolíticos/farmacologia , Proteínas de Bactérias/química , Desenho de Fármacos , Proteínas de Helminto/química , Humanos , Hormônios de Invertebrado/química , Estrutura Molecular , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
[structure: see text] A new strategy for the synthesis of peptidyl and peptidomimetic P1-aldehydes 3 on HCAM solid support is described. The appropriate C-terminal aldehyde precursors were prepared and anchored to a resin support via a semicarbazone linkage (HCAM resin). After synthetic elaboration, acidic hydrolysis efficiently delivered C-terminal target aldehydes 3a-h in good overall yields and in excellent purity.
