ABSTRACT
Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.
Subject(s)
Amidines/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Oxazines/chemical synthesis , Administration, Oral , Amidines/chemistry , Amidines/pharmacology , Animals , Benzoxazines , Biological Availability , Combinatorial Chemistry Techniques , Dogs , Drug Design , Fibrinolysin/antagonists & inhibitors , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Injections, Intravenous , Models, Molecular , Oxazines/chemistry , Oxazines/pharmacology , Rabbits , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacologyABSTRACT
Utilizing X-ray crystallography and molecular modeling, highly potent and selective peptidomimetic thrombin inhibitors have been designed containing a rigid piperazinedione template. The synthesis and biological activity of these compounds will be described.
Subject(s)
Antithrombins/chemical synthesis , Drug Design , Piperazines/chemistry , Antithrombins/chemistry , Antithrombins/pharmacology , Crystallography, X-Ray , Models, MolecularABSTRACT
Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.
