Cyclic and linear oligocarbamate ligands for human thrombin

Several classes of compounds have been tested as potential inhibitors of th e serine protease thrombin, an important regulator of blood coagulation cas cades. We describe here the discovery of a new class of thrombin inhibitors based on an unnatural carbamate biopolymer. Oligocarbamate thrombin inhibi tors were identified through the screening of diverse cyclic trimer, cyclic tetramer, and linear tetramer libraries using the one bead, one peptide me thod. Whereas the cyclic trimer oligocarbamate ligands bound thrombin with modest affinity, a cyclic tetramer oligocarbamate inhibited thrombin with a n apparent Ki of 31 nM. Linear oligocarbamate tetramers bound thrombin with inhibition constants in the 100-nM range. These nonpeptidic, oligomeric mo lecules may provide the basis for further drug development and studies of t hrombin-ligand interactions. (C) 1999 Published by Elsevier Science Ltd. Al l rights reserved.