Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of invivo efficacy

Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic ent ities 2 and 3 and through SAR additivity studies of the new structural elem ents identified. X-ray crystallographic studies of 4b-thrombin complex reve aled a hydrophobic and an electrostatic interaction of these new elements w ith thrombin at the S-2 and S-3 binding sites. In vitro and in vivo pharmac ological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombo sis. (C) 1999 Elsevier Science Ltd. All rights reserved.