Active site-directed thrombin inhibitors-II. Studies related to arginine/guanidine bioisosteres Original Research Article

A series of N-arylsulfonylarginine amides was synthesized wherein the guanidine or arginine moiety was isosterically replaced by a number of heterocyclic functionalities. These compounds were evaluated as potential active-site inhibitors of thrombin. Bisamidines 11a-n showed a similar SAR to that of simple arginine compounds. The ex vivo clotting time measurement of 11d after ip dosing showed prolongation of clotting time in rats. Isosteric replacement of the guanidine/arginine moiety in N-arylsufonylarginine amides was examined. The chemistry and biological activity of a series of isosteres are also discussed.