Novel angiotensin type 2 (at2) receptor agonists and uses thereof

Abstract

The invention relates to novel pharmaceutically-useful peptides, in particular cyclic peptides that are agonists of the AngII type 2 receptor (AT2 receptor). The invention further relates to the use of such peptides as medicaments, to pharmaceutical compositions containing them, and to their production.

1 . A cyclic peptide compound consisting of the amino acid sequence Xaa 1 -Asp-Arg-Ile/Val-Xaa 5 -Ile/Val-His-Xaa 8  comprising a thioether-bridge linkage between the side chains of Xaa 5  and Xaa 8  such that Xaa 5  and Xaa 8  together form a structure according to either one of the general formula: 
       
         
           
           
               
               
           
         
         wherein R, R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from —H, a lower (e.g. C 1 -C 10 ) alkyl or aralkyl group, preferably wherein R, R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from H and CH 3 , 
         and wherein Xaa 1  is selected from the group consisting of charged amino acids, aromatic amino acids and hydrophobic amino acids and protease-resistant variants thereof, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . Pharmaceutical composition comprising a peptide compound according to  claim 1 , and a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         3 . A method for treating or preventing a condition in which selective agonism of the AT2 receptor is desired and/or required, said method comprising administering a peptide compound of  claim 1 . 
     
     
         4 . A method for synthesizing an AT2 receptor agonist, said method comprising extending a thioether-cyclized peptide analog of Ang(1-7) with an additional amino acid at its N-terminus in a biological system. 
     
     
         5 . The method of  claim 4  wherein the biological system comprises a lantibiotic enzyme system. 
     
     
         6 . The method of  claim 4  wherein the biological system comprises a bacterial host cell. 
     
     
         7 . The method of  claim 4  wherein the AT2 receptor agonist comprises a cyclic peptide compound consisting of the amino acid sequence Xaa 1 -Asp-Arg-Ile/Val-Xaa 5 -Ile/Val-His-Xaa 8  comprising a thioether-bridge linkage between the side chains of Xaa 5  and Xaa 8  such that Xaa 5  and Xaa 8  together form a structure according to one of the general formula 
       
         
           
           
               
               
           
         
         wherein R, R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of —H and a C 1 -C 10  alkyl or aralkyl group, 
         and wherein Xaa 1  is selected from the group consisting of charged amino acids, aromatic amino acids and hydrophobic amino acids and protease-resistant variants thereof selected from D-stereoisomer or cyclized residue, 
       
     
     
         8 . The method of  claim 4  wherein the AT2 receptor agonist comprises a cyclic peptide compound consisting of the amino acid sequence Xaa 1 -Asp-Arg-Ile/Val-Xaa 5 -Ile/Val-His-Xaa 8  comprising a thioether-bridge linkage between the side chains of Xaa 5  and Xaa 8  such that Xaa 5  and Xaa 8  together form a structure according to the general formula