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

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

doi:10.1016/j.bmcl.2018.09.001

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

Bioorg Med Chem Lett. 2018 Nov 1;28(20):3372-3375. doi: 10.1016/j.bmcl.2018.09.001. Epub 2018 Sep 5.

Authors

Imadul Islam¹, Shendong Yuan², Christopher W West², Marc Adler³, Ulrich Bothe⁴, Judi Bryant², Zheng Chang², Kieu Chu⁵, Kumar Emayan², Giovanna Gualtieri², Elena Ho⁶, David Light⁷, Cornell Mallari⁶, John Morser⁸, Gary Phillips², Caralee Schaefer⁶, Drew Sukovich⁵, Marc Whitlow³, Deborah Chen², Brad O Buckman²

Affiliations

¹ Medical Core Facility and Research Platforms, King Abdullah International Medical Research Center/King Saud Bin, Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia; Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. Electronic address: [email protected].
² Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
³ Department of Biophysics, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
⁴ Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States; Research and Development Pharmaceutical, Bayer AG, 13342 Berlin, Germany.
⁵ Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
⁶ Department of Animal Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
⁷ Department of Antibody Technology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
⁸ Cardiovascular Department, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.

PMID: 30201291
DOI: 10.1016/j.bmcl.2018.09.001

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.

Keywords: Multiple sclerosis; Serine protease; Urokinase; uPA; uPA inhibitor.

MeSH terms

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

Substances

Benzylamines
Serine Proteinase Inhibitors
Urokinase-Type Plasminogen Activator