THROMBIN INHIBITORS BASED ON KETONE DERIVATIVES OF ARGININE AND LYSINE

Much attention is currently focused on inhibitors of thrombin as poten tial anticoagulants. We have previously reported thrombin inhibitors b ased on fragments of fibrinogen containing a ketomethylene isostere at P-1 - P'(1). We now expand on these early findings by reporting on tr ipeptide based inhibitors of thrombin containing arginine or lysine ke tones at the C-terminus. A large variety of such ketones have been stu died and compared in their ability to increase the thrombin lime in hu man plasma. In the case of arginine or lysine ketones the order of act ivity (i.e. decreasing IC50 TT) was: alkylketones < beta-ketoesters < difluoro beta-ketoamides < alkyloxymethyl ketones < fluoroketones. Lys ine analogues were generally found to be ca. ten-fold less active than their arginine counterparts. However, in the case of alpha-ketoesters the lysine derivatives were superior to all the types of arginine ket ones studied (including the arginine alpha-keto ester derived thrombin inhibitor). A mechanistic explanation of the relative inactivity of t he arginine alpha-keto ester derivative is proposed. All the highly el ectrophilic ketones were found to be slow-binding wih thrombin.