Abstract
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
MeSH terms
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Administration, Oral
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Alkaloids / chemical synthesis*
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Alkaloids / chemistry
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Alkaloids / pharmacology
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Animals
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Biological Availability
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Chromatography, High Pressure Liquid
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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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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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In Vitro Techniques
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Macaca fascicularis
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Platelet Aggregation Inhibitors / chemical synthesis
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Receptor, PAR-1 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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4-(5-(3-trifluoromethylphenyl)pyridin-2-yl)ethenyl-3-methyldecahydronaphtho(2,3-c)furan-1(3H)-one
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Alkaloids
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Fibrinolytic Agents
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Furans
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Heterocyclic Compounds, 3-Ring
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Naphthalenes
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Piperidines
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Platelet Aggregation Inhibitors
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Pyridines
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Receptor, PAR-1
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himbacine