Exploring the chiral space within the active site of alpha-thrombin with aconstrained mimic of D-Phe-Pro-Arg - Design, synthesis, inhibitory activity, and x-ray structure of an enzyme-inhibitor complex

An indolizidinone motif with strategically placed substitutents was designe d and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar in hibition of a-thrombin validates the design elements in this inhibitor whic h also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable c hanges in positions. (C) 2000 Elsevier Science Ltd. All rights reserved.