title: Identification of novel inhibitors of urokinase via NMR-based screening.
abstract: Using an NMR-based screen, a novel class of urokinase inhibitors were identified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a guanidine or amidine group. However, unlike previously described guanidino- or amidino-based inhibitors which have pK(a) values greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties which could increase the bioavailability of inhibitors which contain this moiety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase reveals the electrostatic and hydrophobic interactions that stabilize complex formation and suggests nearby subsites that may be accessed to increase the potency of this new series of urokinase inhibitors.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: S
authors.initials: S
authors.lastname: Boyd
authors.forename: D
authors.initials: D
authors.lastname: Nettesheim
authors.forename: V
authors.initials: V
authors.lastname: Nienaber
authors.forename: J
authors.initials: J
authors.lastname: Severin
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Davidson
authors.forename: T
authors.initials: T
authors.lastname: Rockway
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D014568:Urokinase-Type Plasminogen Activator