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  • Title: Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives.
    Author: Sall DJ, Bailey DL, Bastian JA, Buben JA, Chirgadze NY, Clemens-Smith AC, Denney ML, Fisher MJ, Giera DD, Gifford-Moore DS, Harper RW, Johnson LM, Klimkowski VJ, Kohn TJ, Lin HS, McCowan JR, Palkowitz AD, Richett ME, Smith GF, Snyder DW, Takeuchi K, Toth JE, Zhang M.
    Journal: J Med Chem; 2000 Feb 24; 43(4):649-63. PubMed ID: 10691691.
    Abstract:
    A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
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