1. Discovery of nor-seco himbacine analogs as thrombin receptor antagonists
- Author
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Mariappan V. Chelliah, Tze-Ming Chan, Yan Xia, George Boykow, Madhu Chintala, Matthew Bryant, Ho-Sam Ahn, Keith Eagen, Jacqueline Agans-Fantuzzi, William J. Greenlee, Yunsheng Hsieh, and Samuel Chackalamannil
- Subjects
Blood Platelets ,Platelet Aggregation ,Metabolite ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,Naphthalenes ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alkaloids ,Piperidines ,In vivo ,Drug Discovery ,Thrombin receptor ,medicine ,Animals ,Humans ,Structure–activity relationship ,Receptor, PAR-1 ,Furans ,Molecular Biology ,Vorapaxar ,Drug discovery ,Organic Chemistry ,Thrombin ,Rats ,Macaca fascicularis ,chemistry ,Himbacine ,Molecular Medicine ,Platelet Aggregation Inhibitors ,Ex vivo ,Protein Binding ,medicine.drug - 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.
- Published
- 2012
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