Abstract
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.
MeSH terms
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Administration, Oral
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Animals
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Arterial Occlusive Diseases / complications
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Brain Infarction / drug therapy
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Brain Infarction / etiology
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Brain Infarction / pathology
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Cerebral Arterial Diseases / complications
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Factor Xa / chemistry
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Factor Xa Inhibitors*
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / pharmacology
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Humans
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Injections, Intravenous
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Macaca fascicularis
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Middle Cerebral Artery
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Models, Molecular
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Structure-Activity Relationship
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Tetrahydroisoquinolines / chemical synthesis*
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacology
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Venous Thrombosis / drug therapy
Substances
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4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate
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Factor Xa Inhibitors
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Fibrinolytic Agents
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Isoquinolines
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Piperidines
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Pyridines
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Tetrahydroisoquinolines
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Factor Xa