Matriptase, a
trypsin-like serine protease, which may be involved in tissue remodeling,
cancer invasion, and
metastasis. Potent and selective
matriptase inhibitors not only would be useful pharmacological tools for further elucidation of the role of
matriptase in these processes but also could have therapeutic potential for the treatment and/or prevention of
cancers. We report herein the structure-based approach for the discovery of bis-
benzamidines as a novel class of potent
matriptase inhibitors. The lead compound,
hexamidine (1), inhibits not only the proteolytic activity of
matriptase, (K(i) = 924 nM) but also of
thrombin K(i) = 224 nM). By testing several available analogues, we identified a new analogue (7) that has a K(i) = 208 nM against
matriptase and has only weak inhibitory activity against
thrombin (K(i) = 2670 nM), thus displaying a 13-fold selectivity toward
matriptase. Our results demonstrated that structure-based database screening is effective in the discovery of
matriptase inhibitors and that bis-
benzamidines represent a class of promising
matriptase inhibitors that can be used for further
drug design studies. Finally, our study suggested that there is sufficient structural differences between
matriptase and its closely related
serine proteases, such as
thrombin, for the design of potent and selective
matriptase inhibitors.