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.

Predicting subsite interactions of plasmin with substrates and inhibitors through computational docking analysis

“…The protein data bank (PDB) IDs used in this study were 2FX6 for trypsin in complex with 2-aminobenzimidazole 11 , 1BML for plasmin in complex with streptokinase and no ligand molecules 12 , and 1FV9 for (micro) urokinase in complex with 2-amino-5-hydroxy-benzimidazole 13 . As described in the Introduction section, the X-ray structure of plasmin complexed with a covalently bound ligand is available with PDB ID 1BUI 9 .…”

Recent advances inde novodesign strategy for practical lead identification

“…47 From outstanding profiles of SAR by NMR described above, the success rate of de novo design of novel lead compounds will be dramatically enhanced. In fact, novel active ligands for at least six different kinds of proteins (FK506 binding protein (FKBP), 41 human papillomavirus E2 protein, 42 Stromelysin, 43 Erm methyltransferase, 44 Urokinase, 45 and Adenosine kinase 46 ) have already been identified through SAR by NMR (two examples are shown in Fig. 2).…”

Formation of nitrogen‐containing heterocycles using di(imidazole‐1‐yl)methanimine

“…Collectively, these examples suggest that the cyclization reaction using 1 may occur with a wide diversity of starting anilines under mild conditions. Given the example that 2-aminobenzimidazole is an attractive template for urokinase inhibitors [6], the reaction with 1 could be useful in the formation of many bioactive heterocyclic compounds.…”