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Publication Details

Title :

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

Journal:

Bioorg Med Chem Lett.

Impact Factor:

2.42

Authors:

Islam I1, Yuan S2, West CW2, Adler M3, Bothe U4, Bryant J2, Chang Z2, Chu K5, Emayan K2, Gualtieri G2, Ho E6, Light D7, Mallari C6, Morser J8, Phillips G2, Schaefer C6, Sukovich D5, Whitlow M3, Chen D2, Buckman BO2.

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: imadulislam@yahoo.com.

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.

Year of Publication:

2018

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.