Novel, Potent Non-Covalent Thrombin Inhibitors Incorporating P3-Lactam Scaffolds

Evolution of P1-argininal inhibitor prototypes led to a series of non-covalent P3-7-membered lactam inhibitors 1a–w, featuring novel peptidomimetic units that probe each of the S1, S2, and S3 specificity pockets of thrombin. Rigid P1-arginine surrogates possessing a wide range of basicity (calcd pKaʹs neutral–14) were surveyed. The design, synthesis, and biological activity of these targets are presented.