3-amidinophenylalanine-based inhibitors of urokinase

Synthesis and anti-uPA activity of a series of N alpha-triisopropyl-phenyls ulfonyl-protecte 3-amidinophenylalanine amides are described. We have explo red SAR around the C-terminal amide part for inhibition of uPA, plasmin and trypsin. Modification of the amide part has been found to affect potency b ut not selectivity. With a K-i of 0.41 mu M 2r-L is one of the most potent uPA inhibitors described so far. The X-ray crystal structure of 2r-L was so lved in complex with trypsin, superimposed with uPA and the results suggest an unique binding mode of this inhibitor type. (C) 1999 Published by Elsev ier Science Ltd. All rights reserved.