Discovery of a factor Xa inhibitor (3 R,4 R)-1-(2,2-difluoro-ethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloro-pyridin-2-yl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} as a clinical candidate

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 17; pp. 5313 - 5319
• Main Authors: Anselm, Lilli, Banner, David W., Benz, Jörg, Groebke Zbinden, Katrin, Himber, Jacques, Hilpert, Hans, Huber, Walter, Kuhn, Bernd, Mary, Jean-Luc, Otteneder, Michael B., Panday, Narendra, Ricklin, Fabienne, Stahl, Martin, Thomi, Stefan, Haap, Wolfgang
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2010; Elsevier
• Subjects: Anticoagulation; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa inhibitors; Medical sciences; Pharmacology. Drug treatments; Structure based design; X-ray analysis; Anticoagulation; X-ray analysis; Structure based design; Factor Xa inhibitors; Pyridone derivatives; Serine endopeptidases; Enzyme; Enzyme inhibitor; Amides; Coagulation Factor Xa; Anticoagulant; Pyrrolidine derivatives; Pyridine derivatives; Peptidases; Structure activity relation; Chlorine Organic compounds; Hydrolases; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.126

A series of (3 R,4 R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.