Synthesis, evaluation, and crystallographic analysis of L-371,912: A potent and selective active-site thrombin inhibitor.

Abstract Removal of the β-ketoamide functionality from L-370,518 (K i = 0.09 nM) provided a 5 nM K i inhibitor of thrombin: L-371,912. Comparison of the enzyme-inhibitor crystal structures suggests a possible explanation for the relatively small change in affinity for thrombin. L-371,912 is selective for thrombin over related serine proteases and is efficacious in an animal model of arterial thrombosis.