Abstract
Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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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Animals
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Biological Availability
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Blood Platelets / drug effects
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Blood Platelets / physiology
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Drug Discovery
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Furans / chemical synthesis*
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Furans / pharmacokinetics
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Humans
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Macaca fascicularis
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Naphthalenes / chemical synthesis*
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Naphthalenes / pharmacokinetics
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Platelet Aggregation / drug effects*
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Platelet Aggregation Inhibitors / chemical synthesis*
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Platelet Aggregation Inhibitors / pharmacokinetics
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Protein Binding
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Rats
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Receptor, PAR-1 / antagonists & inhibitors*
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Structure-Activity Relationship
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Thrombin / metabolism
Substances
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Alkaloids
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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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Thrombin
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himbacine