Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 21; pp. 5952 - 5958
• Main Authors: Shi, Yan, Sitkoff, Doree, Zhang, Jing, Han, Wei, Hu, Zilun, Stein, Philip D., Wang, Ying, Kennedy, Lawrence J., O’Connor, Stephen P., Ahmad, Saleem, Liu, Eddie C.-K., Seiler, Steve M., Lam, Patrick Y.S., Robl, Jeffrey A., Macor, John E., Atwal, Karnail S., Zahler, Robert
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.2007; Elsevier
• Subjects: Aminomethyl pyrrolidines; Bioisosterism; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa inhibitor; Factor Xa Inhibitors; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Piperazine; Pyrrolidines - chemistry; Scaffold; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Aminomethyl pyrrolidines; Bioisosterism; Scaffold; Piperazine; Factor Xa inhibitor; Nitrogen heterocycle; Coagulation Factor Xa; Anticoagulant; Modeling; Pyrrolidine derivatives; Pyridine derivatives; Thiophene derivatives; Structure activity relation; Molecular model; Antithrombotic agent; Sulfonamide; Serine endopeptidases; Enzyme; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Peptidases; Sulfur heterocycle; Hydrolases; Carboxamide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.07.063

The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC 50 of 5.5 nM and PT EC 2x of 1.7 μM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.