Co-agonists at glp-1 and gip receptors suitable for oral delivery

Abstract

Peptide co-agonists of the human GLP-1 and GIP receptors suitable for oral delivery, including long-acting derivatives, and their medical use in treatment and/or prevention of obesity, diabetes, and/or liver diseases are described.

1 . A compound comprising a peptide and a substituent; wherein the amino acid sequence of the peptide is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO.: 47) 
                 
                     
                   YX 2 EGTX 6 TSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FX 23   
                 
                     
                     
                 
                     
                   X 24 WLLX 28 GX 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39   
                 
             
                
                
                
                
               
            
           
         
         with an optional amide modification of the C-terminus, wherein 
         X 2  is Aib or A 
         X 6  is F or V 
         X 12  is I or Y 
         X 13  is Y, A, L, or I 
         X 16  is K or E 
         X 20  is Q, R, E, or H 
         X 21  is A or E 
         X 23  is I or V 
         X 24  is E, Q, or N 
         X 28  is A or R 
         X 30  is G or absent 
         X 31  is P or absent 
         X 32  is E, S or absent 
         X 33  is S, K or absent 
         X 34  is G or absent 
         X 35  is A or absent 
         X 36  is P or absent 
         X 37  is P or absent 
         X 38  is P or absent 
         X 39  is S or absent; 
         and wherein the substituent is attached to the peptide via Lysine (K) at position 16 or 33; 
         or a pharmaceutically acceptable salt hereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein X 32 X 33 X 34 X 35  is selected from the group consisting of SSGA (SEQ ID NO.: 40), ESGA (SEQ ID NO.: 41), and SKGA (SEQ ID NO.: 42). 
     
     
         3 . The compound according to  claim 1 , wherein the amino acid sequence of the peptide is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO.: 37) 
                 
                     
                   YX 2 EGTX 6 TSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FX 23 X 24   
                 
                     
                     
                 
                     
                   WLLX 28 GGPSSGAPPPS; 
                 
             
                
                
                
                
               
            
           
         
         wherein 
         X 2  is Aib or A 
         X 6  is F or V 
         X 12  is I or Y 
         X 13  is Y, A, L, or I 
         X 16  is K or E 
         X 20  is Q, R, E, or H 
         X 21  is A or E 
         X 23  is I or V 
         X 24  is E, Q, or N 
         X 28  is A or R. 
       
     
     
         4 . The compound according to  claim 1 , wherein X 13 LEX 16 QAAX 20 X 21 FX 23 X 24  is selected from the group consisting of LLEKQAAREFIN (SEQ ID NO.: 43), LLEKQAAREFIE (SEQ ID NO.: 44), LLEKQAAQEFIE (SEQ ID NO.: 45) and LLEEQAAREFIE (SEQ ID NO.: 46). 
     
     
         5 . The compound according to  claim 1 , wherein the amino acid sequence of the peptide is selected from the group consisting of SEQ ID NO.: 1-27 and 33-35. 
     
     
         6 . The compound according to  claim 5 , wherein the peptide has the amide modification of the C-terminus. 
     
     
         7 . The compound according to  claim 1 , wherein the substituent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A method for treating a liver disorder, comprising administering to a patient in need thereof the compound according to  claim 1 , wherein the liver disorder is selected from the group consisting of hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) liver inflammation, and fatty liver. 
     
     
         14 . A peptide having the amino acid sequence 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO.: 47) 
                 
                     
                   YX 2 EGTX 6 TSDYSX 12 X 13 LEX 16 QAAX 20 X 21 FX 23 X 24   
                 
                     
                     
                 
                     
                   WLLX 28 GX 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39   
                 
             
                
                
                
                
               
            
           
         
         with an optional amide modification of the C-terminus; wherein 
         X 2  is Aib or A 
         X 6  is F or V 
         X 12  is I or Y 
         X 13  is Y, A, L, or I 
         X 16  is K or E 
         X 20  is Q, R, E, or H 
         X 21  is A or E 
         X 23  is I or V 
         X 24  is E, Q, or N 
         X 28  is A or R 
         X 30  is G or absent 
         X 31  is P or absent 
         X 32  is E, S or absent 
         X 33  is S, K or absent 
         X 34  is G or absent 
         X 35  is A or absent 
         X 36  is P or absent 
         X 37  is P or absent 
         X 38  is P or absent 
         X 39  is S or absent. 
       
     
     
         15 . The peptide according to  claim 14 , wherein the amino acid sequence of the peptide is selected from the group consisting of SEQ ID NO.: 1-27 and 33-35. 
     
     
         16 . The peptide according to  claim 14 , wherein the amino acid sequence is SEQ ID NO.: 34.