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Thrombin Inhibitors Based on Ketone Derivatives of Arginine and Lysine

1995; Volume: 9; Issue: 1 Linguagem: Inglês

10.3109/14756369509040680

8755-5093

D. Michael Jones, Butrus Atrash, Hamish Ryder, Ann‐Catrine Teger‐Nilsson, Erica Gyzander, Michael Szelke,

Chemical Reaction Mechanisms

Much attention is currently focused on inhibitors of thrombin as potential anticoagulants. We have previously reported thrombin inhibitors based on fragments of fibrinogen containing a ketomethylene isostere at P1-P'1′ We now expand an these early findings by reporting on tripeptide based inhibitors of thrombin containing arginine or lysine ketones at the C-terminus. A large variety of such ketones have been studied and compared in their ability to increase the thrombin time in human plasma. In the case of arginine or lysine ketones the order of activity (i.e. decreasing IC50 TT) was: alkyl ketones <β-ketoesters < difluoro β-ketoamides < alkyloxymethyl ketones < fluoroketones. Lysine analogues were generally found to be ca. ten-fold less active than their arginine counterparts. However, in the case of α-ketoesters the lysine derivatives were superior to all the types of arginine ketones studied (including the arginine α-keto ester derived thrombin inhibitor). A mechanistic explanation of the relative inactivity of the arginine α-keto ester derivative is proposed. All the highly electrophilic ketones were found to be slow-binding wih thrombin.