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

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

Journal article

Peer reviewed

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, …

Bioorganic & medicinal chemistry letters, Vol.28(20), pp.3372-3375

01/11/2018

DOI: https://doi.org/10.1016/j.bmcl.2018.09.001

PMID: 30201291

Abstract

Multiple sclerosis

Serine protease

uPA

uPA inhibitor

Urokinase

[Display omitted] •Design and synthesis of benzylamine based selective and orally available inhibitors of uPA has been described.•Prior knowledge of SAR has been used to optimize the lead compounds.•Structure based drug design and modeling afforded analogs with acceptable drug like properties.•Compound 824859 shows efficacy in acute and chronic EAE model for multiple sclerosis.•This may represents new therapeutic strategy to treat MS using small molecule uPA inhibitors. 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.

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Title: Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis
Creators - without role: Imadul Islam - King Saud bin Abdulaziz University for Health Sciences
Shendong Yuan - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Christopher W. West - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Marc Adler - Department of Biophysics, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Ulrich Bothe - Bayer
Judi Bryant - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Zheng Chang - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Kieu Chu - Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Kumar Emayan - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Giovanna Gualtieri - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Elena Ho - Department of Animal Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
David Light - Department of Antibody Technology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Cornell Mallari - Department of Animal Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
John Morser - Cardiovascular Department, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Gary Phillips - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Caralee Schaefer - Department of Animal Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Drew Sukovich - Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Marc Whitlow - Department of Biophysics, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Deborah Chen - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Brad O. Buckman - Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Publication Details: Bioorganic & medicinal chemistry letters, Vol.28(20), pp.3372-3375
Publisher: Elsevier Ltd
Identifiers: 9921857608331
Academic Unit: King Saud Bin Abdulaziz University for Health Sciences
Language: English
Resource Type: Journal article