Prodrug compound comprising a therapeutic agent, an oligopeptide with a non-genetically encoded amino acid, a stabilizing group and optionally a linker group

摘要

A compound comprises: (1) a therapeutic agent; (2) an oligopeptide having a formula (AA)n-AA4-AA3-AA2-AA1, wherein each AA represents an amino acid; n is 0-16; AA4 represents a non-genetically encoded amino acid; AA3 is selected from leucine, tyrosine, phenylalanine, p-Cl-phenylalanine, p-nitrophenylalanine, valine, norleucine, norvaline, phenylglycine, tryptophan, tetrahydroisoquinoline-3-carboxylic acid, 3-pyridylanine, alanine, glycine, thienylalanine, methionine, valine and proline; AA2 is selected from alanine, leucine, tyrosine, glycine, serine, 3-pyridylalanine, 2- thienylalanine, aminoisobutyric acid, threonine and phenylalanine; and AA1 is selected from leucine, phenylalanine, isoleucine, alanine, glycine, tyrosine, 2-napthylalanine, serine, and b-alanine; and (3) a stabilizing group that hinders cleavage of said oligopeptide by enzymes present in whole blood; wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and AA1 of the oligopeptide is directly linked to the therapeutic agent or indirectly linked through a linker group not cleavable by trouase to the therapeutic agent at a second attachment site of the oligopeptide and wherein the compound is selectively cleavable by an enzyme associated with a target cell. The compounds can be used in the manufacture of a medicament and decreases the toxicity of the therapeutic agent.