Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)

The discovery, synthesis, and early SAR work on a benzyl amine containing series of uPA inhibitors is reported. In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.