STRUCTURAL MODIFICATION OF AN ORALLY-ACTIVE THROMBIN INHIBITOR, LB30057 - REPLACEMENT OF THE D-POCKET-BINDING NAPHTHYL MOIETY

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (K-i = 0.38 nM), selective, and orally active thrombin inhibito r. As a continuation of studies into benzamidrazone-based thrombin inh ibitors, we have structurally modified compound 2 by replacing the nap hthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin an d oral absorption. The highest activity was obtained with compound 23 (K-i = 0.045 nM). (C) 1998 Elsevier Science Ltd. All rights reserved.