RESUMO
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
Assuntos
Fator IXa/antagonistas & inibidores , Isoxazóis/química , Animais , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fator IXa/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Simulação de Dinâmica Molecular , Tempo de Tromboplastina Parcial , Estrutura Terciária de Proteína , Tempo de Protrombina , Ratos , Relação Estrutura-AtividadeRESUMO
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
