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

Abstract Potent, subnanomolar thrombin inhibitors 4 , 5 , and 6 are developed through side chain optimization of novel, benzo[ b ]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b -thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S 2 and S 3 binding sites. In vitro and in vivo pharmacological studies showed that 4 , 5 , and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.