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

A systematic investigation of the structure-activity relationships of the C -3 side chain of the screening hit la led to the identification of the pote nt thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases i n potency over the starting lead la. This activity enhancement was accompli shed with an increase of thrombin selectivity. The in vitro anticoagulant p rofiles of derivatives 28c and 31c were determined, and they compare favora bly with the clinical agent H-R-1-[4aS,-8aS]perhydroisoquinolyl-prolyl-argi nyl 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 thrombosi s and were found to be efficacious in reducing clot formation. However, the ir efficacy is currently limited by their rapid and extensive distribution following administration.