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

•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.