RESUMEN
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.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Factor IXa/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Humanos , Estructura Molecular , RatasRESUMEN
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.