Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 14; pp. 3784 - 3788
• Main Authors: Watson, Nigel S., Brown, David, Campbell, Matthew, Chan, Chuen, Chaudry, Laiq, Convery, Máire A., Fenwick, Rebecca, Hamblin, J. Nicole, Haslam, Claudine, Kelly, Henry A., King, N. Paul, Kurtis, Cynthia L., Leach, Andrew R., Manchee, Gary R., Mason, Andrew M., Mitchell, Charlotte, Patel, Champa, Patel, Vipulkumar K., Senger, Stefan, Shah, Gita P., Weston, Helen E., Whitworth, Caroline, Young, Robert J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.07.2006; Elsevier
• Subjects: Administration, Oral; Animals; Antithrombin III - chemical synthesis; Antithrombin III - pharmacology; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Pyrrolidinones - chemical synthesis; Pyrrolidinones - pharmacology; Rats; Rats, Wistar; Thrombin - drug effects; Factor Xa; Rat; Nitrogen heterocycle; Lactam; Coagulation Factor Xa; Non peptide compound; Anticoagulant; Selectivity; Morpholine derivatives; Modeling; Structure activity relation; Chlorine Organic compounds; Molecular model; Antithrombotic agent; Bicyclic compound; Chemical synthesis; Dog; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Peptidomimetic compound; Rodentia; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Bioavailability; Condensed benzenic compound; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Carboxamide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.04.053

The synthesis is reported of the potent, selective fXa inhibitor 24 which shows highly encouraging rat and dog pharmacokinetic profiles and excellent oral bioavailability. A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.