At4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agents

Abstract

AT 4 receptor agonists are potent activators of angiogenesis and can be used to treat diseases that are characterized by vascular insufficiency. AT 4 receptor antagonists, which are potent inhibitors of angiogenesis, and can be used as anti-angiogenic agents for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerotic plaque formation, and any disease process that is characterized by excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells.

1 . An AT 4  receptor ligand comprising a compound of the formula:
   R 1 ZR 2 R 3 X,   wherein R 1  is selected from the group consisting of: Leu and norleucine;   Z is a peptide bond or a reduced peptide bond;   R 2  is Tyr;   R 3  is selected from the group consisting of: Leu and Ile;   X is selected from the group consisting of: nothing, ZR 4 , ZR 4 —R 5 , and ZR 4 —R 5 —R 6 , wherein Z is a peptide bond or a reduced peptide bond;   R 4  is selected from the group consisting of: hexamide, His, and Sar;   R 5  is selected from the group consisting of: Pro, Sar, and Phe;   R 6  is selected from the group consisting of: dPhe and amide group.   
     
     
         2 . The composition according to  claim 1 , wherein the compound has the formula: Nle-Y—I—(CH 2 ) 6 -amide. 
     
     
         3 . The composition according to  claim 1 , wherein the compound has the formula: Nle-Y—I—H. 
     
     
         4 . The composition according to  claim 1 , wherein the compound has the formula: Nle 1 -Leu 3 -(CH 2 NH 2 ) 3-4  -AngIV. 
     
     
         5 . The composition according to  claim 1 , wherein the compound has the formula: L-Ψ-Y-L-Ψ-H-P-F. 
     
     
         6 . The composition according to  claim 1 , wherein the compound has the formula: Nle-Y—I—(CH 2 ) 6 —F-amide. 
     
     
         7 . The composition according to  claim 1 , wherein the compound has the formula: Nle-Y-I-Sar-Sar-dPhe. 
     
     
         8 . A method selected from the group consisting of: (a) a method for inhibiting the growth and metastasis of a non-solid tumor; (b) a method for inhibiting the growth and metastasis of melanoma; and (c) a method for altering MMP expression in pathologies associated with over expression or under expression of matrix metalloproteinase enzymes, comprising administering at least one AT 4  receptor ligand, wherein the ligand comprises a compound of the formula:
   R 1 ZR 2 R 3 X,   wherein R 1  is selected from the group consisting of: Leu and norleucine;   Z is a peptide bond or a reduced peptide bond;   R 2  is Tyr;   R 3  is selected from the group consisting of: Leu and Ile;   X is selected from the group consisting of: nothing, ZR 4 , ZR 4 —R 5 , and ZR 4 —R 5 —R 6 , wherein Z is a peptide bond or a reduced peptide bond;   R 4  is selected from the group consisting of: hexamide, His, and Sar;   R 5  is selected from the group consisting of: Pro, Sar, and Phe;   R 6  is selected from the group consisting of: dPhe and amide group.   
     
     
         9 . A method for inhibiting extracellular matrix deposition by a cell comprising administering at least one AT 4  ligand, wherein the ligand comprises a compound of the formula:
   R 1 ZR 2 R 3 X,   wherein R 1  is selected from the group consisting of: Leu and norleucine;   Z is a peptide bond or a reduced peptide bond;   R 2  is Tyr;   R 3  is selected from the group consisting of: Leu and Ile;   X is selected from the group consisting of: nothing, ZR 4 , ZR 4 —R 5 , and ZR 4 —R 5 —R 6 , wherein Z is a peptide bond or a reduced peptide bond;   R 4  is selected from the group consisting of: hexamide, His, and Sar;   R 5  is selected from the group consisting of: Pro, Sar, and Phe;   R 6  is selected from the group consisting of: dPhe and amide group.   
     
     
         10 . The method according to  claim 9 , wherein inhibition of extracellular matrix deposition comprises inhibition of at least one of endothelial cell growth and vessel formation.