| 摘要 |
<p>The invention provides compounds which specifically inhibit factor Xa activity. The compounds consist of the structure X1-R1-R2-R3-X2, wherein X1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl, 1-methylbutyl, 2,2-dimethylpentyl, 2,2-dimethylpropyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl, methyl-cyclohexyl and cycloprpoyl- methylene, formyl, acetyl, benzoyl, benzyl, picolyl, R1 is Tyr, R2 is Ile, R3 is Arg, and X2 is an oral ester selected from the group consisting of methoxymethyl, ethoxymethyl, iso-propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, alpha-acetoxymethyl, ethoxycarbonyl-1-methyl, alpha-acetoxyethyl, 3-phthalidyl, 5,6-dimethylphthalidyl, 1-(ethoxycarbonyloxy)eth-1- yl, and 1-(methylaminocarbonyloxy)eth-1-yl. 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 the use of compounds for the preparation of a pharmaceutical composition for 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.</p> |
