Design and construction of novel thrombin inhibitors featuring P3–P4 quaternary lactam dipeptide surrogates

Potent serine protease inhibitor 1a featuring a hybrid P3–P4 quaternary lactam dipeptide surrogate was prepared based upon SAR and molecular modeling investigations and in order to further probe the S2/S3 thrombin and FXa subsites. An efficient and concise synthetic route to the key aminolactam intermediate 4 was developed. The design, synthesis, and biological activity of this target and its P3–P4 diastereomer 1b is presented.