US2023272029A1PendingUtilityA1

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

Assignee: NOVO NORDISK ASPriority: Jul 22, 2020Filed: Jul 22, 2021Published: Aug 31, 2023
Est. expiryJul 22, 2040(~14 yrs left)· nominal 20-yr term from priority
A61K 47/64C07K 14/605A61K 47/542A61K 38/26A61K 38/00C07K 14/001A61P 3/10A61P 3/04A61P 1/16
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Claims

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.

Claims

exact text as granted — not AI-modified
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[H]; 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, or absent, 
         X 33  is S, Kc 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, and 
         X 39  is S or absent; 
         wherein the substituent is attached to the peptide via Lysine (K) at position 16 or 33; 
         and wherein the substituent comprises at least one of HOOC—(CH 2 ) n —CO—, wherein n is 14, 16 or 18; 
         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, ESGA, and SKGA. 
     
     
         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 GGPS 
                 
                     
                     
                 
                     
                   SGAPPPS; 
                 
             
                
                
                
                
               
            
           
         
         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, and 
         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, LLEKQAAREFIE, LLEKQAAQEFIE and LLEEQAAREFIE. 
     
     
         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, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:
 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.   
     
     
         6 . The compound according to  claim 5  wherein the peptide comprises 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: 
       
         
           
           
               
               
           
         
         (Compound No. 1, SEQ ID NO: 1, Substituent: C), 
       
       
         
           
           
               
               
           
         
         (Compound No. 2, SEQ ID NO: 2, Substituent: C), 
       
       
         
           
           
               
               
           
         
         (Compound No. 3, SEQ ID NO: 2, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 4, SEQ ID NO: 3, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 5, SEQ ID NO: 3, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 6, SEQ ID NO: 4, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 7, SEQ ID NO: 4, Substituent: A), 
       
       
         
           
           
               
               
           
         
         No. 8, SEQ ID NO: 5, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 9, SEQ ID NO: 6, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 10, SEQ ID NO: 6, Substituent: A), 
       
       
         
           
           
               
               
           
         
         (Compound No. 11, SEQ ID NO: 5, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 12, SEQ ID NO: 7, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 13, SEQ ID NO: 8, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 14, SEQ ID NO: 9, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 15, SEQ ID NO: 10, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 16, SEQ ID NO: 5, Substituent: C), 
       
       
         
           
           
               
               
           
         
         (Compound No. 17, SEQ ID NO: 11, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 18, SEQ ID NO: 12, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 19, SEQ ID NO: 13, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 20, SEQ ID NO: 14, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 21, SEQ ID NO: 15, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 22, SEQ ID NO: 16, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 23, SEQ ID NO: 17, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 24, SEQ ID NO: 18, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 26, SEQ ID NO: 20, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 27, SEQ ID NO: 21, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 28, SEQ ID NO: 22, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 29, SEQ ID NO: 23, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 30, SEQ ID NO: 24, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 31, SEQ ID NO: 25, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 32, SEQ ID NO: 25, Substituent: A), 
       
       
         
           
           
               
               
           
         
         (Compound No. 33, SEQ ID NO: 26, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 34, SEQ ID NO: 27, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 35, SEQ ID NO: 10, Substituent: A), 
       
       
         
           
           
               
               
           
         
         (Compound No. 36, SEQ ID NO: 27, Substituent: A), 
       
       
         
           
           
               
               
           
         
         (Compound No. 42, SEQ ID NO: 33, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 43, SEQ ID NO: 34, Substituent: B), 
       
       
         
           
           
               
               
           
         
         (Compound No. 44, SEQ ID NO: 35, Substituent: B) 
       
       
         
           
           
               
               
           
         
         (Compound No. 45, SEQ ID NO: 34, Substituent: A), 
       
       
         
           
           
               
               
           
         
         (Compound No. 46, SEQ ID NO: 34, Substituent: E), and 
       
       
         
           
           
               
               
           
         
         (Compound No. 47, SEQ ID NO: 34, Substituent: E). 
       
     
     
         9 . (canceled) 
     
     
         10 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         11 - 13 . (canceled) 
     
     
         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 28G X 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 L, 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, and 
         X 39  is S or absent. 
       
     
     
         15 . The peptide according to  claim 14  where the amino acid sequence of the peptide is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.

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