PREPARATION OF ARGATROBAN ANALOG THROMBIN INHIBITORS WITH REDUCED BASIC GUANIDINE MOIETY, AND STUDIES OF THEIR CELL-PERMEABILITY AND ANTITHROMBOTIC ACTIVITIES

To improve the oral absorption of thrombin inhibitors, Argatroban anal ogs 1, 2, 3 and 4, with reduced guanidine basicity were prepared. The in vitro thrombin inhibitory potency and their permeability of the Cac o-2 cell monolayers were studied as a model for intestinal permeabilit y. While the neutral molecule 2 was quite permeable through the Caco-2 cell monolayers the other charged compounds 1, 3, 4 and 5 did not hav e appreciable permeability. Interestingly, the N-hydroxyguanidine comp ound 4 maintains potent intrinsic activity, which implies that the N-h ydroxyguanidine can be used in this series of compounds as a guanidine surrogate with reduced basicity.