Identification of novel inhibitors of urokinase via NMR-based screening.

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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

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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