Acylated Exendin-4 Compounds

Abstract

This invention provides new therapeutic peptides, i.e. new protracted Exendin-4 compounds, pharmaceutical compositions and the use of such.

1 . A compound comprising an amino acid sequence of formula (I):
   Xaa 1 -Xaa 2 -Glu-Gly-Thr-Xaa 6 -Thr-Ser-Asp-Leu-Ser-Xaa 12 -Gln-Xaa 14 -Glu-Xaa 16 -Xaa 17 -Ala-Val-Xaa 20 -Xaa 21 -Phe-Ile-Xaa 24 -Trp-Leu-Xaa 27 -Xaa 28 -Xaa 29 -Gly-Pro-Xaa 32 -Ser-Xaa 34 -Ala-Pro-Pro-Pro-Xaa 39 .  Formula (I) (SEQ ID No: 1)   
       wherein
 Xaa 1  is L-histidine, imidazoylpropionyl, D-histidine, desamino-histidine, 2-amino-histidinehomohistidine, N α -acetyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine, 
 Xaa 2  is Ala, Gly or Aib; 
 Xaa 6  is Phe or α-methyl-Phe; 
 Xaa 12  is Lys, Arg or Gln; 
 Xaa 14  is Leu, Lys, Met, Ile or Nle; 
 Xaa 16  is Gly, Glu or Aib; 
 Xaa 17  is Gln or Glu; 
 Xaa 20  is Lys, Glu or Arg; 
 Xaa 21  is Glu or Leu; 
 Xaa 24  is Ala, Glu or Arg; 
 Xaa 27  is Val, Lys, Gln or Arg; 
 Xaa 28  is Lys, Leu, Glu, Asn, Gln or Arg; 
 Xaa 29  is Gly, Ala or Aib; 
 Xaa 32  is Ser or Lys; 
 Xaa 34  is Gly or Lys; 
 Xaa 39  is Ser or O-Benzyl-Ser 
 the C-terminal may optionally be derivatized as an amide; 
 and wherein one lysine selected from Lys12, Lys14, Lys20, Lys27, Lys28, Lys32 or Lys 34 in formula I is derivatized with A-(B) r —(C) s — to give an acylated Lys residue, 
 wherein C, which is independently selected s times, where s is 0, 1, 2, 3 or 4, is represented by: 
 
       
         
           
           
               
               
           
         
         wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 and n is 1, 2, 3 or 4; 
         and wherein B is a group selected r times, where r is 0, 1, 2 or 3, from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and 
         wherein A is a group selected from 
       
       
         
           
           
               
               
           
         
       
       where l is 12, 13, 14, 15, 16, 17, 18, 19 or 20
 with the proviso that at least two amino acids selected from Xaa 1 , Xaa 2 , Xaa 6 , Xaa 12 , Xaa 14 , Xaa 16 , Xaa 17 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 27 Xaa 28 , Xaa 29 , Xaa 32 , Xaa 34  and Xaa 39  are different from the corresponding amino acids in exendin-4, 
 
     
     
         2 . A compound according to  claim 1  wherein
 Xaa 1  is L-histidine, imidazoylpropionyl or des-amino Histidine;   Xaa 2  is Gly or Aib;   Xaa 6  is Phe or α-methyl-Phe;   Xaa 12  is Lys, Arg or Gln;   Xaa 14  is Leu, Lys or Met;   Xaa 16  is Glu;   Xaa 17  is Glu;   Xaa 20  is Lys;   Xaa 21  is Leu;   Xaa 24  is Glu;   Xaa 27  is Val, Lys, Gln or Arg;   Xaa 28  is Lys, Leu, Glu, Asn, Gln or Arg;   Xaa 29  is Gly or Ala;   Xaa 32  is Ser or Lys;   Xaa 34  is Gly or Lys;   Xaa 39  is Ser or O-Benzyl-Ser   the C-terminal may optionally be derivatized as an amide;   and wherein one lysine selected from Lys12, Lys14, Lys20, Lys27, Lys28, Lys32 or Lys 34 in formula I is derivatized with A-(B) r —(C) s — to give an acylated Lys residue,   wherein C, which is independently selected s times, wherein s is 0, 1, 2, 3 or 4, is represented by:   
       
         
           
           
               
               
           
         
         wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 and n is 1, 2 or 3; 
         and wherein B is a group selected r times, where r is 0, 1, 2 or 3, from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and 
         wherein A is a group selected from 
       
       
         
           
           
               
               
           
         
       
       where l is 12, 13, 14, 15, 16, 17, 18, 19 or 20
 with the proviso that at least two amino acids selected from Xaa 1 , Xaa 2 , Xaa 6 , Xaa 12 , Xaa 14 , Xaa 16 , Xaa 17 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 27 Xaa 28 , Xaa 29 , Xaa 32 , Xaa 34  and Xaa 39  are different from the corresponding amino acid acids in exendin-4, 
 
     
     
         3 . A compound according to  claim 1 , wherein Xaa 14  is Leu or Lys; 
     
     
         4 . A compound according to  claim 2 , wherein Xaa 14  is Leu; 
     
     
         5 . A compound according to  claim 1 , wherein Xaa 14  is Lys and wherein said Lys14 is derivatized with A-(B) r —(C) s — to give an acylated Lys residue. 
     
     
         6 . A compound according to  claim 1 , wherein Xaa 28  is Gln, Leu, Arg, or Lys; 
     
     
         7 . A compound according to  claim 1 , wherein Xaa 29  is Ala; 
     
     
         8 . A compound according to  claim 1 , wherein r is 1; 
     
     
         9 . A compound according to  claim 1 , wherein s is 2, 
     
     
         10 . A compound according to  claim 1 , wherein p is 1. 
     
     
         11 . A compound according to  claim 1 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound according to any of the claims above  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 1 , wherein l is 13, 14, 15, 16, 17 or 18; 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method for treating a subject suffering from hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease, Alzheimer's, stroke, inflammatory bowel syndrome, dyspepsia or gastric ulcers, said method comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of  claim 14 . 
     
     
         19 . A method for delaying or preventing disease progression in type 2 diabetes in a subject, said method comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of  claim 14 .