Sulfonamidolactam inhibitors of coagulation factor Xa

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 7; pp. 2428 - 2433
• Main Authors: Smallheer, Joanne M., Wang, Shuaige, Laws, Mia L., Nakajima, Suanne, Hu, Zilun, Han, Wei, Jacobson, Irina, Luettgen, Joseph M., Rossi, Karen A., Rendina, Alan R., Knabb, Robert M., Wexler, Ruth R., Lam, Patrick Y.S., Quan, Mimi L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2008; Elsevier
• Subjects: Anticoagulant; Anticoagulants - chemical synthesis; Anticoagulants - pharmacology; Antithrombotic; Binding Sites; Biological and medical sciences; Blood Coagulation Tests; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa Inhibitors; Lactams - chemical synthesis; Lactams - pharmacology; Ligands; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Piperidones - chemical synthesis; Piperidones - pharmacology; Serine protease inhibitors; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Serine protease inhibitors; Anticoagulant; Factor Xa inhibitors; Antithrombotic; Lactam; Coagulation Factor Xa; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Antithrombotic agent; Colon; Chemical synthesis; Human; Pyridone derivatives; Sulfonamide; Cell permeability; Serine endopeptidases; Enzyme; Enzyme inhibitor; In vitro; Peptidases; Cell line; Hydrolases; Thienopyridine derivative; Protease inhibitor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.02.054

The synthesis and SAR of N-aryl-3-(arylsulfonylamino)-piperidone inhibitors of Factor Xa is described. Compound 55 is a representative example of this series with fXa K i = 0.043 nM. As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.