Factor Xa inhibitors

Abstract

The invention provides compounds which specifically inhibit factor Xa activity. The compounds consist of the structure X1-YIR-X2, wherein X1 is H, acyl, alkyl, acylalkyl, arylalkyl or one or more amino acids, and X2 is a modified C-terminal group, one or more carboxy-protecting groups or one or more amino acids or other substituent, and Y, I and R are tyrosine, isoleucine and arginine, respectively, or peptidomimetic or organic structures that possess the same functional activity as Y, I and R, respectively. In addition, the present invention provides a compound having the structure A1-A2-(A3)m-B, where m is 0 or 1. A compound of the invention can be linear or cyclic and can be about 2 and 43 residues in length. A compound of the invention is characterized, in part, in that it exhibits a specific inhibition of factor Xa activity with a ki of <= 100 mu M, preferably <= 2 nM, and does not substantially inhibit the activity of other proteases involved in the coagulation cascade. The invention further provides methods of specifically inhibiting the activity of factor Xa and of inhibiting blood clotting in vitro and in an individual and methods of detecting factor Xa levels or activity.

Description

field of invention [0001] The present invention relates generally to inhibitors of coagulation proteins, and more particularly to specific inhibitors of thrombin factor Xa. Background of the invention [0002] The ability to form blood clots is crucial for survival. However, in certain diseased states, the formation of coagulation in the circulatory system is itself a source of morbidity. Therefore, it may sometimes be desirable to prevent the formation of clots, however, complete inhibition of the coagulation system is not desirable because life-threatening bleeding would occur. [0003] In order to reduce the formation of blood coagulation in blood vessels, those skilled in the art have been trying to develop an effective inhibitor of prothrombinase or factor Xa, and this inhibitor is bound to the prothrombinase complex, so that the process of blood coagulation Activation of thrombin. [0004] Once threshold concentrations of thrombin are reached, factor Xa inhibitors a...

AI Technical Summary

Problems solved by technology

A major disadvantage of both inhibitors is the need for repeated dosing, which creates antibodies that disable them, limiting their usefulness in the clinic

Additionally, the size of TAP and ATS makes oral administration impossible, further limiting the number of patients who can benefit from these agents

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