Amino acid and peptide conjugates of amiloride and methods of use thereof

Abstract

The present invention provides compositions comprising amiloride amino acid and peptide conjugates. Efficient methods are also provided for administering the amiloride conjugates of the present invention for treating cancer or a central nervous system disease or disorder or for preventing or reducing ischemia-reperfusion injury. Further, kits are provided for the treatment of a central nervous system disease or disorder or for the prevention or reduction of ischemia-reperfusion injury using the amiloride conjugates of the present invention.

1 - 63 . (canceled) 
     
     
         64 . A method for treating cancer in a subject in need thereof, said method comprising:
 administering to said subject a therapeutically effective amount of a conjugate having the formula:   
       
         
           
           
               
               
           
         
       
       wherein
 X is n independently selected amino acids; and 
 n is an integer greater than or equal to 1. 
 
     
     
         65 . The method of  claim 64 , wherein said cancer is a glioma or breast cancer. 
     
     
         66 . The method of  claim 64 , wherein X is a peptide and n is greater than 1. 
     
     
         67 . The method of  claim 66 , wherein said peptide is selectively cleaved by a peptidase. 
     
     
         68 . The method of  claim 67 , wherein said peptidase releases a proteolytic product. 
     
     
         69 . The method of  claim 68 , wherein said proteolytic product is amiloride or C5am-Gly. 
     
     
         70 . The method of  claim 67 , wherein said peptidase is selected from the group consisting of an opioid neuropeptide peptidase, a metalloproteinase, a plasminogen activator, a cathepsin, a calpain, and a caspase. 
     
     
         71 - 124 . (canceled) 
     
     
         125 . The method of  claim 64 , wherein X is an amino acid attached at the N-terminus, selected from the group consisting of glycine, phenylalanine, (2,4-dichloro)-phenylalanine, serine, and O-benzyl serine. 
     
     
         126 . The method of  claim 125 , wherein X is O-benzyl serine, attached at its N-terminus. 
     
     
         127 . The method of  claim 64 , wherein X is a peptide attached at the N-terminus, beginning with a glycine residue, to the carboxylic terminus of which a peptide selected from the group consisting of SEQ ID NOS:2 to 7 and 41 is attached at its N-terminus. 
     
     
         128 . The method of  claim 65 , wherein X is an amino acid attached at the N-terminus, selected from the group consisting of glycine, phenylalanine, (2,4-dichloro)-phenylalanine, serine, and O-benzyl serine. 
     
     
         129 . The method of  claim 128 , wherein X is O-benzyl serine, attached at its N-terminus. 
     
     
         130 . The method of  claim 128 , wherein X is a peptide attached at the N-terminus, beginning with a glycine residue, to the carboxylic terminus of which a peptide selected from the group consisting of SEQ ID NOS:2 to 7 and 41 is attached at its N-terminus. 
     
     
         131 . A method for treating a central nervous system disease or disorder in a subject in need thereof, said method comprising:
 administering to said subject a therapeutically effective amount of a conjugate having the formula:   
       
         
           
           
               
               
           
         
       
       wherein
 X is a peptide comprising n independently selected amino acids; 
 n is an integer greater than 1; and 
 said peptide is selectively cleaved by a peptidase in the central nervous system. 
 
     
     
         132 . The method of  claim 131 , wherein said peptidase releases a proteolytic product. 
     
     
         133 . The method of  claim 131 , wherein said proteolytic product is amiloride or C5a/w-Gly. 
     
     
         134 . The method of  claim 131 , wherein said peptidase is selected from the group consisting of an opioid neuropeptide peptidase, a metalloproteinase, a plasminogen activator, a cathepsin, a calpain, and a caspase. 
     
     
         135 . The method of  claim 131 , wherein X is an amino acid attached at the N-terminus, selected from the group consisting of glycine, phenylalanine, (2,4-dichloro)-phenylalanine, serine, and O-benzyl serine. 
     
     
         136 . The method of  claim 131 , wherein X is O-benzyl serine, attached at its N-terminus. 
     
     
         137 . The method of  claim 131 , wherein said central nervous system disease or disorder is selected from the group consisting of brain edema, traumatic brain injury, tissue hypoxia-ischemia, ischemia-reperfusion injury, epilepsy, brain tumor, and stroke. 
     
     
         138 . The method of  claim 137 , wherein X is an amino acid attached at the N-terminus, selected from the group consisting of glycine, phenylalanine, (2,4-dichloro)-phenylalanine, serine, and O-benzyl serine. 
     
     
         139 . The method of  claim 137 , wherein X is O-benzyl serine, attached at its N-terminus.