Discovery of nor-seco himbacine analogs as thrombin receptor antagonists
| Autor: | 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, Samuel Chackalamannil |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
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 |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:2544-2549 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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