A series of lactam derivatives 1b-g featuring P4-o-alkoxycarbonylbenzylsulfonamide residues along with the potential P4-homosaccharin prodrug candidate 1h was prepared in order to probe the thrombin S3 specificity pocket. The synthesis and alkoxide-catalyzed ring opening of the novel homosaccharin intermediate 7 followed by subsequent elaboration delivered the targets 1b-h which were potent and selective thrombin inhibitors. The design, synthesis, and biological activity of these targets will be presented.