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

• Published in: Journal of medicinal chemistry Vol. 48; no. 19; pp. 5900 - 5908
• Main Authors: Roehrig, Susanne, Straub, Alexander, Pohlmann, Jens, Lampe, Thomas, Pernerstorfer, Josef, Schlemmer, Karl-Heinz, Reinemer, Peter, Perzborn, Elisabeth
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.09.2005; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Anticoagulants - chemical synthesis; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Chemistry, Medicinal; Crystallography, X-Ray; Dogs; Factor Xa Inhibitors; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Half-Life; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Models, Molecular; Morpholines - chemical synthesis; Morpholines - pharmacokinetics; Morpholines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prothrombin Time; Rats; Rats, Wistar; Rivaroxaban; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; DRUG DESIGN; CRYSTAL-STRUCTURES; POTENT; COAGULATION-FACTOR XA; ANTICOAGULANTS; Intravenous administration; Rat; Molecular structure; Coagulation Factor Xa; Anticoagulant; Morpholine derivatives; Thiophene derivatives; Structure activity relation; Antithrombotic agent; Dog; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Bioavailability; Organic chlorine compounds; X ray diffraction; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Oxazolidinone derivative; Hydrolases; Carboxamide; Pharmacokinetics; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050101d

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.