Inhibitors of the urokinase receptor

Abstract

The present invention concerns peptides as inhibitors of the binding of urokinase to the urokinase receptor. The peptides, which are preferably cyclic, are suitable as pharmaceutical agents for diseases that are mediated by urokinase and its receptor.

1 . A method of inhibiting the binding of at least one urokinase plaminogen activator to at least one urokinase plaminogen activator receptor in a patient in need of such inhibition comprising: 
 administering to said patient a peptide comprising monomeric building blocks and having the general structural formula (I):                          (SEQ ID NO:4    in which    X 21  to X 30  each denotes an aminocarboxylic acid and    X 21  and X 29  are bridged together,    Y is a spacer group that can couple the peptide to carrier substances    n and m are each independently 0 or 1,    and the monomeric building blocks are linked by —NR 1 CO— or —CONR 1 — bonds where R 1  in each case independently denotes hydrogen, methyl or ethyl,    and wherein the amino acid residues X 21 -X 30  each independently have one of the following meanings:    (i) X 21  and X 29  are each independently an aminocarboxylic acid residue with an SH side chain or X 21  and X 29  are together two aminocarboxylic acid residues which are bridged by a thioether bond;    (ii) X 22  and X 27  are each independently an aminocarboxylic acid residue with an aliphatic side chain;    (iii) X 23  is an aminocarboxylic acid residue with a basic or an aliphatic hydrophilic side chain;    (iv) X 24 , X 25  and X 30  are each independently an aminocarboxylic acid residue with an aromatic side chain,    (v) X 26  is an aminocarboxylic acid residue with an aliphatic side chain, and    (vi) X 28  is an aminocarboxylic acid residue with an aliphatic side chain;    and a pharmaceutically compatible salt or derivative thereof, wherein said derivative comprises a peptide of formula I in which reactive groups of a side chain and/or of the N-terminus or C-terminus have been subjected to one or more modifications, said modifications being selected from the group consisting of acylation, amidation and esterification of carboxylic acid groups.    
     
     
         2 . The method of  claim 1 , wherein X 21  and X 29  are bridged via a disulfide bond.  
     
     
         3 . A peptide comprising monomeric building blocks and having the general structural formula (II):  
       X 1 —[X 2 ] n —[X 3 ] m —X 4 —K—Y—F—X 5 —X 6 —I—X 7 —W—[X 8 ] r   (II)  
       wherein, 
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are each independently an aminocarboxylic acid,  
 n, m and r are each independently 0 or 1,  
 K is an α-aminocarboxylic acid with a lysine side chain,  
 F is an α-aminocarboxylic acid with a phenylalanine side chain,  
 I is an α-aminocarboxylic acid with an isoleucine side chain,  
 w is α-aminocarboxylic acid with a tryptophan side chain,  
 and the monomeric building blocks are linked by —NR 1 CO— or —CONR 1 — bonds,  
 wherein R 1  in each case independently denotes hydrogen, methyl or ethyl, or pharmaceutically compatible salts and derivatives thereof,  
 wherein  
 at least one of the amino acid residues X 1 , X 2 , X 3 , X 6 , I, X 7 , W and X 8  is a D-amino acid residue.  
 
     
     
         4 . The peptide of  claim 3 , wherein 
 the monomeric building blocks X 1  and X 7 , or X 1  and X 8  are bridged together.    
     
     
         5 . A pharmaceutical composition comprising at least one peptide of  claim 3  and a pharmaceutical acceptable carrier thereof, and optionally at least one auxiliary agent and/or diluent.  
     
     
         6 . A method of inhibiting the binding of at least one urokinase plaminogen activator to at least one urokinase plaminogen activator receptor in a patient in need of such inhibition comprising: 
 administering to said patient at least one peptide of  claim 3  in a binding of urokinase plaminogen activator to urokinase plaminogen activator receptor inhibting amount.    
     
     
         7 . The peptide or of  claim 3 , wherein X 1  and X 8  are (a) each independently an aminocarboxylic acid residue with an SH side chain or (b) are aminocarboxylic acid residues which are adapted to be bridged by a thioether bond.  
     
     
         8 . The peptide of  claim 7 , wherein X 1  and X 8  are bridged via a disulfide bond formed between said SH side chains.  
     
     
         9 . The peptide of  claim 7 , wherein X 1  and X 8  are bridged via a thioether bond.  
     
     
         10 . The peptide of  claim 3 , wherein X 2  is an aminocarboxylic acid residue with an aliphatic and uncharged side chain.  
     
     
         11 . The peptide of  claim 10 , wherein said chain is a valine, leucine or isoleucine side chain.  
     
     
         12 . The peptide of  claim 3 , wherein X 3  and X 5  are each independently an aminocarboxylic acid residue with an aliphatic hydrophilic side chain.  
     
     
         13 . The peptide of  claim 12 , wherein said side chain is a serine or threonine side chain.  
     
     
         14 . The peptide of  claim 3 , wherein X 4  and X 6  are each independently an aminocarboxylic acid residue with an aliphatic hydrophilic side chain.  
     
     
         15 . The peptide of  claim 14 , wherein said side chain is an amide side chain.  
     
     
         16 . The peptide of  claim 15 , wherein said side chain is an asparagine or glutamine side chain.  
     
     
         17 . The peptide of  claim 3 , wherein X 1  and X 7  are each independently (a) a basic aminocarboxylic acid residue or (b) an aminocarboxylic acid residue with a SH side chain.  
     
     
         18 . The peptide of  claim 17  wherein said basic aminocarboxylic acid residue is histidine.  
     
     
         19 . The peptide of  claim 17  wherein said side chain in (b) is a cysteine side chain.  
     
     
         20 . The peptide of  claim 19  wherein X 1  and X 7  are bridged via a disulfide bridge.  
     
     
         21 . The method of  claim 6 , wherein said peptide is an antagonist of urokinase plaminogen activator.  
     
     
         22 . The method of  claim 6 , wherein said patient suffers from a disease associated with the expression of urokinase plaminogen activator receptor.  
     
     
         23 . The method of  claim 22 , wherein said disease is a tumor.  
     
     
         24 . The method of  claim 6 , wherein said at least one peptide is administered to said patient via a targeting vehicle.  
     
     
         25 . A targeting vehicle comprising at least one peptide of  claim 3 .  
     
     
         26 . The targeting vehicle of  claim 25 , wherein said targeting vehicle is a viral vector or a liposome.  
     
     
         27 . The peptide of  claim 2 , wherein X 21  and X 29  are bridged via a disulfide bond.  
     
     
         28 . The method of  claim 1 , wherein said peptide is a cyclic peptide and acts as an urokinase plaminogen activator antagonist.  
     
     
         29 . The method of  claim 1 , wherein said peptide is administered to said patient via a targeting vehicle.  
     
     
         30 . The method of  claim 1 , wherein said patients suffers from a disease associated with the expression of urokinase plaminogen activator receptor.  
     
     
         31 . The method of  claim 30 , wherein said disease is a tumor.  
     
     
         32 . The method of  claim 31 , wherein said peptide is part of (or is coupled to) a polypeptide.  
     
     
         33 . (New) A targeting vehicle comprising a polypeptide comprising (or having coupled thereto) at least one peptide having the general structural formula (I):  
       
         
           
           
               
               
           
         
         (SEQ ID NO:4  
         in which  
         X 21  to X 30  each denotes an aminocarboxylic acid and  
         X 21  and X 29  are bridged together,  
         Y is a spacer group that can couple the peptide to carrier substances  
         n and m are each independently 0 or 1,  
         and the monomeric building blocks are linked by —NR 1 CO— or —CONR 1 — bonds where R 1  in each case independently denotes hydrogen, methyl or ethyl,  
         and wherein the amino acid residues X 21 —X 30  each independently have one of the following meanings:  
         (i) X 21  and X 29  are each independently an aminocarboxylic acid residue with an SH side chain or X 21  and X 29  are together two aminocarboxylic acid residues which are bridged by a thioether bond;  
         (ii) X 22  and X 27  are each independently an aminocarboxylic acid residue with an aliphatic side chain;  
         (iii) X 23  is an aminocarboxylic acid residue with a basic or an aliphatic hydrophilic side chain;  
         (iv) X 24 , X 25  and X 30  are each independently an aminocarboxylic acid residue with an aromatic side chain,  
         (v) X 26  is an aminocarboxylic acid residue with an aliphatic side chain, and  
         (vi) X 28  is an aminocarboxylic acid residue with an aliphatic side chain;  
         and a pharmaceutically compatible salt or derivative thereof, wherein said derivative comprises a peptide of formula I in which reactive groups of a side chain and/or of the N-terminus or C-terminus have been subjected to one or more modifications, said modifications being selected from the group consisting of acylation, amidation and esterification of carboxylic acid groups.