Design, synthesis, and structure–Activity relationships of unsubstituted piperazinone-Based transition state factor Xa inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 4; pp. 723 - 728
• Main Authors: Huang, Wenrong, Naughton, Mary Ann, Yang, Hua, Su, Ting, Dam, Suiko, Wong, Paul W., Arfsten, Ann, Edwards, Susan, Sinha, Uma, Hollenbach, Stanley, Scarborough, Robert M., Zhu, Bing-Yan
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 24.02.2003; Elsevier
• Subjects: Animals; Anticoagulants - chemical synthesis; Anticoagulants - pharmacokinetics; Biological and medical sciences; Blood Coagulation Tests; Blood. Blood coagulation. Reticuloendothelial system; Drug Design; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - pharmacokinetics; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Thrombosis - prevention & control; Intravenous administration; Rat; Nitrogen heterocycle; Thiazole derivatives; Lactam; Rabbit; Cardiovascular disease; Coagulation Factor Xa; Non peptide compound; Anticoagulant; Selectivity; Vascular disease; Structure activity relation; Chlorine Organic compounds; Six membered ring; Chemical synthesis; Sulfur nitrogen heterocycle; Sulfonamide; Serine endopeptidases; Enzyme; Peptidomimetic compound; Rodentia; Benzene derivatives; Enzyme inhibitor; Guanidines; Lagomorpha; In vitro; Thrombosis; Peptidases; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Bolus injection; Treatment; Animal; Transition state; Hydrolases; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)01037-5

A series of novel transition state factor Xa inhibitors containing a variety of lactam ring systems as central templates was synthesized in an expedient manner and allowed for a great deal of structural variability. Among them, the piperazinone-based inhibitors were found to be not only active against factor Xa but also selective over thrombin. Optimization of the P4 moiety yielded several potent compounds with IC 50 below 1 nM against factor Xa. A series of novel transition state factor Xa inhibitors containing a variety of lactam ring systems as central templates was synthesized. Compound 16 displays IC 50 of 2 nM.