Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): An Oral, Direct Factor Xa Inhibitor
| Autor: | Alexander Straub, Thomas Lampe, Josef Pernerstorfer, Jens Pohlmann, Karl-Heinz Schlemmer, Elisabeth Perzborn, Susanne Roehrig, Peter Reinemer |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Models Molecular medicine.drug_mechanism_of_action medicine.drug_class Stereochemistry Morpholines Factor Xa Inhibitor Administration Oral Biological Availability Carboxamide Thiophenes In Vitro Techniques Crystallography X-Ray Structure-Activity Relationship Dogs Fibrinolytic Agents Rivaroxaban Drug Discovery Antithrombotic medicine Animals Humans Structure–activity relationship Rats Wistar biology Chemistry Anticoagulants Stereoisomerism Ligand (biochemistry) Rats Bioavailability Enzyme inhibitor Prothrombin Time biology.protein Molecular Medicine Factor Xa Inhibitors Half-Life medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 48:5900-5908 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050101d |
| Popis: | Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases. |
| Databáze: | OpenAIRE |
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