Abstract
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
MeSH terms
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Alkaloids / chemistry*
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Alkaloids / pharmacology*
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Animals
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Anticoagulants / chemistry
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Anticoagulants / pharmacology
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Furans / chemistry*
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Furans / pharmacology*
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Molecular Structure
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology*
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Piperidines / chemistry*
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Piperidines / pharmacology*
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Rats
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Receptor, PAR-1 / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Alkaloids
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Anticoagulants
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Furans
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Naphthalenes
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Piperidines
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Platelet Aggregation Inhibitors
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Receptor, PAR-1
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himbacine