2-Amidino analogs of glycine–amiloride conjugates: Inhibitors of urokinase-type plasminogen activator

The relative non-toxicity of the diuretic amiloride, coupled with its selective inhibition of the protease urokinase plasminogen activator (uPA), makes this compound class attractive for structure–activity studies. Herein we substituted the C(2)-acylguanidine of C(5)-glycyl-amiloride with amidine and amidoxime groups. The data show the importance of maintaining C(5)-hydrophobicity. The C(5)-benzylglycine analogs containing either C(2)-acylguanidine or amidine inhibited uPA with an IC50 ranging from 3 to 7μM and were cytotoxic to human U87 malignant glioma cells.