RESUMEN
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.
Asunto(s)
Factor IXa/antagonistas & inhibidores , Isoxazoles/química , Animales , Sitios de Unión , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Factor IXa/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Isoxazoles/metabolismo , Isoxazoles/farmacología , Simulación de Dinámica Molecular , Tiempo de Tromboplastina Parcial , Estructura Terciaria de Proteína , Tiempo de Protrombina , Ratas , Relación Estructura-ActividadRESUMEN
CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.