ABSTRACT
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.
Subject(s)
Factor IXa/antagonists & inhibitors , Isoxazoles/chemistry , Animals , Binding Sites , Blood Coagulation/drug effects , Crystallography, X-Ray , Dogs , Drug Design , Drug Evaluation, Preclinical , Factor IXa/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Isoxazoles/metabolism , Isoxazoles/pharmacology , Molecular Dynamics Simulation , Partial Thromboplastin Time , Protein Structure, Tertiary , Prothrombin Time , Rats , Structure-Activity RelationshipABSTRACT
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.
