Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy |
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| Authors: | Zhang M Bailey D L Bastian J A Briggs S L Chirgadze N Y Clawson D K Denney M L Gifford-Moore D S Harper R W Johnson L M Klimkowski V J Kohn T J Lin H S McCowan J R Richett M E Sall D J Smith A J Smith G F Snyder D W Takeuchi K Utterback B G Yan S C |
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| Institution: | Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. |
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| Abstract: | Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzob]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 S2 and S3 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. |
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