ABSTRACT
Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.
Subject(s)
Aminopyridines/chemistry , Factor VIIa/antagonists & inhibitors , Fibrinolytic Agents/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Thromboplastin/antagonists & inhibitors , Aminopyridines/pharmacology , Binding Sites , Crystallography, X-Ray , Drug Design , Fibrinolytic Agents/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.
Subject(s)
Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/pharmacokinetics , Animals , Drug Design , Half-Life , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Highly selective and potent factor VIIa-tissue factor (fVIIa.TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration-response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox) in the baboon model are also presented.
