Identification of novel inhibitors of urokinase via NMR-based screening.
Article Details
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Hajduk PJ, Boyd S, Nettesheim D, Nienaber V, Severin J, Smith R, Davidson D, Rockway T, Fesik SW
Identification of novel inhibitors of urokinase via NMR-based screening.
J Med Chem. 2000 Oct 19;43(21):3862-6.
- PubMed ID
- 11052791 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 2-Amino-1H-benzimidazol-5-ol Urokinase-type plasminogen activator IC 50 (nM) 10000 N/A N/A Details Amiloride Urokinase-type plasminogen activator IC 50 (nM) 7000 N/A N/A Details