Exploring the chiral space within the active site of α-thrombin with a constrained mimic of -Phe-Pro-Arg — design, synthesis, inhibitory activity, and X-ray structure of an enzyme–inhibitor complex

An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of -Phe-Pro-Arg. Low nanomolar inhibition of α-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with α-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions.