Identification of novel inhibitors of urokinase via NMR-based screening

Using an NMR-based screen, a novel class of urokinase inhibitors were ident ified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a gu anidine or amidine group. However, unlike previously described guanidino- o r amidino-based inhibitors which have pK(a) values greater than 9.0, urokin ase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties wh ich could increase the bioavailability of inhibitors which contain this moi ety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybe nzimidazole, complexed with urokinase reveals the electrostatic and hydroph obic interactions that stabilize complex formation and suggests nearby subs ites that may be accessed to increase the potency of this new series of uro kinase inhibitors.