Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

Abstract

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

• Authors: Imadul Islam, Shendong Yuan, Christopher W West, Marc Adler, Ulrich Bothe, Judi Bryant, Zheng Chang, Kieu Chu, Kumar Emayan, Giovanna Gualtieri, Elena Ho, David Light, Cornell Mallari, John Morser, Gary Phillips, Caralee Schaefer, Drew Sukovich, Marc Whitlow, Deborah Chen, Brad O Buckman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 20 Pg. 3372-3375 (11 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 30201291 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Benzylamines
• Serine Proteinase Inhibitors
• Urokinase-Type Plasminogen Activator

Topics

• Animals
• Benzylamines (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
• Binding Sites
• Female
• Humans
• Mice
• Models, Molecular
• Molecular Structure
• Multiple Sclerosis (drug therapy)
• Rats
• Serine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
• Structure-Activity Relationship
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors, chemistry)