Structure and property based design of factor Xa inhibitors: Biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 28 - 33
• Main Authors: Young, Robert J., Borthwick, Alan D., Brown, David, Burns-Kurtis, Cynthia L., Campbell, Matthew, Chan, Chuen, Charbaut, Marie, Convery, Máire A., Diallo, Hawa, Hortense, Eric, Irving, Wendy R., Kelly, Henry A., King, N. Paul, Kleanthous, Savvas, Mason, Andrew M., Pateman, Anthony J., Patikis, Angela N., Pinto, Ivan L., Pollard, Derek R., Senger, Stefan, Shah, Gita P., Toomey, John R., Watson, Nigel S., Weston, Helen E., Zhou, Ping
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2008; Elsevier
• Subjects: Animals; Anticoagulants - chemistry; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Factor Xa; Factor Xa Inhibitors; Hydrophobic and Hydrophilic Interactions; Male; Medical sciences; Models, Molecular; Oral inhibitors; Pharmacology. Drug treatments; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacokinetics; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacokinetics; Serine Proteinase Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship; Oral inhibitors; Factor Xa; Imidazole derivatives; Intravenous administration; Rat; Coagulation Factor Xa; Anticoagulant; Pyrrolidine derivatives; Thiophene derivatives; Structure activity relation; Chlorine Organic compounds; Antithrombotic agent; Chemical synthesis; Sulfonamide; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Tertiary amine; Hydrolases; Benzenic compound; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.11.019

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.