Abstract
The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
MeSH terms
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Administration, Oral
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Alkaloids / chemical synthesis*
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Alkaloids / pharmacokinetics
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Alkaloids / pharmacology
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Animals
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Furans / chemical synthesis*
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Furans / pharmacokinetics
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Furans / pharmacology
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Humans
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In Vitro Techniques
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Lactones / chemical synthesis*
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Lactones / pharmacokinetics
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Lactones / pharmacology
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Macaca fascicularis
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Naphthalenes / chemical synthesis*
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Naphthalenes / pharmacokinetics
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Naphthalenes / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Platelet Aggregation Inhibitors / chemical synthesis*
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Platelet Aggregation Inhibitors / pharmacokinetics
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Platelet Aggregation Inhibitors / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Receptors, Thrombin / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Alkaloids
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Furans
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Lactones
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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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Receptors, Thrombin
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himbacine
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vorapaxar