RESUMEN
In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/química , Trombina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Perros , Semivida , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Macaca mulatta , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Óxidos/química , Ratas , Solubilidad , Relación Estructura-Actividad , Trombosis/inducido químicamente , Trombosis/tratamiento farmacológicoRESUMEN
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.