Abstract
Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
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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Biological Availability
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Blood Platelets / metabolism
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Furans / chemical synthesis*
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Furans / pharmacokinetics
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Furans / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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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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Isoquinolines / chemical synthesis*
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Isoquinolines / pharmacokinetics
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Isoquinolines / pharmacology
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Macaca fascicularis
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Mice
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Microsomes, Liver / metabolism
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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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Receptor, PAR-1 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Alkaloids
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Furans
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Heterocyclic Compounds, 3-Ring
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Isoquinolines
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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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decahydro-1-methyl-3-oxo-9-(2-(5-(3-fluorophenyl)-2-pyridinyl)ethenyl)furo(3,4-g)isoquinoline-6(3H)-carboxylic acid ethyl ester
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himbacine