RESUMO
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Glicina/análogos & derivados , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombina III/química , Cristalografia por Raios X , Fator Xa/química , Fator Xa/metabolismo , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
Assuntos
Antitrombina III/síntese química , Inibidores do Fator Xa , Corantes Fluorescentes/farmacologia , ortoaminobenzoatos/farmacologia , Anticoagulantes/química , Antitrombina III/química , Sítios de Ligação , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/síntese química , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese químicaRESUMO
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT).