Tripeptide prodrug compounds
First Claim
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1. A compound comprising:
- (1) a therapeutic agent capable of entering a target cell,(2) an oligopeptide of the formula AA3-AA2-AA1 wherein the oligopeptide is selected from the group consisting of;
Leu-Ala-GIy (SEQ ID NO;
10), and Leu-Tyr-Leu (SEQ ID NO;
13);
(3) a stabilizing group;
(4) optionally, a linker group not cleavable by TOP,wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide,wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood, and wherein the compound is cleavable by TOP.
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Abstract
The prodrug of the invention is a modified form of a therapeutic agent and comprises a therapeutic agent, an oligopeptide of three amino acids, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by a trouase enzyme such as Thimet oligopeptidase. Also disclosed are methods of making and using the prodrug compounds.
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Citations
26 Claims
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1. A compound comprising:
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(1) a therapeutic agent capable of entering a target cell, (2) an oligopeptide of the formula AA3-AA2-AA1 wherein the oligopeptide is selected from the group consisting of;
Leu-Ala-GIy (SEQ ID NO;
10), and Leu-Tyr-Leu (SEQ ID NO;
13);(3) a stabilizing group; (4) optionally, a linker group not cleavable by TOP, wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide, wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood, and wherein the compound is cleavable by TOP. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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23. A compound comprising:
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(1) a therapeutic agent capable of entering a target cell, (2) an oligopeptide peptide selected from the group consisting of;
Leu-Ala-GIy (SEQ ID NO;
10), and Leu-Tyr-Leu (SEQ ID NO;
13);3) a stabilizing group, the stabilizing group selected from; (a) a dicarboxylic or higher order carboxylic acid, (b) a non-genetically encoded amino acid having four or more carbons, or (c) one of aspartic acid linked to the oligopeptide at the β
-carboxy group of the aspartic acid or glutamic acid linked to the oligopeptide at the γ
-carboxy group of the glutamic acid, and(4) optionally, a linker group not cleavable by TOP, wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide, wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood, and wherein the compound is cleavable by TOP. - View Dependent Claims (24, 25)
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26. A pharmaceutical composition comprising:
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(1) a compound comprising; (a) a therapeutic agent capable of entering a target cell, (b) an oligopeptide peptide selected from the group consisting of;
Leu-Ala-GIy (SEQ ID NO;
10), and Leu-Tyr-Leu (SEQ ID NO;
13);(c) a stabilizing group, the stabilizing group selected from; (d) optionally, a linker group not cleavable by TOP, wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide, wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood, and wherein the compound is cleavable by TOP, and (2) a pharmaceutically acceptable carrier.
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Specification