Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: Synthesis, stability and biological characterization

We report structure-activity investigations in a series of tripeptide amide inhibitors of thrombin, and the development of a series of highly potent active site directed ol-keto carbonyl inhibitors having the side chain of lysine at P-1. Compounds of this class are unstable by virtue of reactivity at the electrophilic carbonyl and racemization at the adjacent carbon (CH). Modifications of prototype alpha-keto-ester 8a have afforded analogs retaining nanomolar K-i. Optimal potency and stability have been realized in alpha-keto-amides 11b (K-i = 2.8 nM) and 11c (K-i = 0.25 nM).