Truncated glp-1 derivaties and their therapeutical use

Abstract

The invention relates to truncated GLP-1 analogues, in particular a GLP-1 analogue which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogues and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.

1 . A GLP-1 analogue which is a modified GLP-1(7-35) (SEQ ID No 1) having:
 i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including   a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and   b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35);   or a derivative thereof.   
     
     
         2 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acid(s) at a position equivalent to position 30, 31, 32, 33, 34, or 35 of GLP-1(7-35) are absent, provided that if the amino acid at position 30, 31, 32, 33, or 34 is absent then each amino acid residue downstream is also absent. 
     
     
         3 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the GLP-1 analogue comprises i) a C-terminal carboxylic acid group; or iii) a C-terminal amide group. 
     
     
         4 . The GLP-1 analogue or derivative thereof according to  claim 1 , which is derivatised with an albumin binding residue or is pegylated. 
     
     
         5 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acid at position 35 is absent, and wherein the total length of the GLP-1 analogue is 28 amino acids. 
     
     
         6 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acids at position 34 and 35 are absent, and wherein the total length of the GLP-1 analogue is 27 amino acids. 
     
     
         7 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acids at position 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 26 amino acids. 
     
     
         8 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acids at position 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 25 amino acids. 
     
     
         9 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acids at position 31, 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 24 amino acids. 
     
     
         10 . The GLP-1 analogue or derivative thereof according to  claim 1 , wherein the amino acids at position 30, 31, 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 23 amino acids. 
     
     
         11 . The GLP-1 analogue or derivative thereof according to  claim 1  having a sequence according to formula (I) 
       
         
           
                 
               
                   (SEQ ID No: 2) 
                 
                   Xaa 7 -Xaa 8 -Xaa 9 -Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -Ser- 
                 
                     
                 
                   Xaa 18 -Tyr-Xaa 20 -Glu-Glu-Xaa 23 -Xaa 24 -Xaa 25 -Arg- 
                 
                     
                 
                   Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -R 
                 
                     
                 
                   Formula (I) 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid; 
         Xaa 9  is Glu or a Glu derivative such as alpha, alpha dimethyl-Glu; 
         Xaa 16  is Val or Leu; 
         Xaa 18  is Ser, Lys, Cys or Arg; 
         Xaa 20  is Leu, Lys or Cys; 
         Xaa 23  is Gln, Glu, Lys, Cys or Arg; 
         Xaa 24  is Ala or Asn; 
         Xaa 25  is Ala or Val; 
         Xaa 27  is Glu, Ala or Leu; 
         Xaa 30  is Ala, Glu, Lys, Arg or absent; 
         Xaa 31  is Trp, Lys, Cys or absent; 
         Xaa 33  is Val, Lys, Cys or absent; 
         Xaa 34  is Lys, Glu, Asn, Arg, Cys or absent; 
         Xaa 35  is Gly, Aib or absent; 
         R is amide or is absent; 
         provided that if Xaa 30 , Xaa 31 , Xaa 32 , Xaa 33 , or Xaa 34  is absent then each amino acid residue downstream is also absent. 
       
     
     
         12 . The GLP-1 analogue or derivative thereof according to  claim 1  having a sequence according to formula (II) 
       
         
           
                 
                 
               
                     
                   (SEQ ID No: 3) 
                 
                     
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser- 
                 
                     
                     
                 
                     
                   Xaa 18 -Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Arg-Glu-Phe- 
                 
                     
                     
                 
                     
                   Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 -R 
                 
                     
                     
                 
                     
                   Formula (II) 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid; 
         Xaa 18  is Ser, Lys or Arg; 
         Xaa 30  is Ala, Glu, Lys, Arg or is absent; 
         Xaa 33  is Val, Lys or absent; 
         Xaa 34  is Lys, Glu, Arg or is absent; 
         Xaa 35  is Gly, Aib or is absent; 
         R is amide or is absent. 
       
     
     
         13 . The GLP-1 derivative according to  claim 1 , wherein at least one amino acid residue is derivatised with A-B-C-D-
 wherein A- is selected from the group consisting of   
       
         
           
           
               
               
           
         
         wherein n is selected from the group consisting of 14, 15, 16 17, 18 and 19, p is selected from the group consisting of 10, 11, 12, 13 and 14, and d is selected from the group consisting of 0, 1, 2, 3, 4 and 5, 
         -B- is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and y is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, 
         -C- is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein b and e are each independently selected from the group consisting of 0, 1 and 2, and c and f are each independently selected from the group consisting of 0, 1 and 2 with the proviso that b is 1 or 2 when c is 0, or b is 0 when c is 1 or 2, and e is 1 or 2 when f is 0, or e is 0 when f is 1 or 2, and 
         -D- is attached to said amino acid residue and is a linker. 
       
     
     
         14 . The GLP-1 derivative according to  claim 13 , wherein D is selected from the group consisting of 
       
         
           
           
               
               
           
         
         and wherein k is selected from the group consisting of 0, 1, 2, 3, 4, 5, 11 and 27, and m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6. 
       
     
     
         15 . The GLP-1 analogue or derivative thereof according to  claim 1 , which is selected from the following:
 [Glu22,Arg26]GLP-1(7-33)amide   N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Glu30,Lys33)GLP-1(7-33)amide;   N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Arg26,Glu30)GLP-1(7-33)amide;   [Glu22,Val25,Arg26]GLP-1(7-33)amide;   [Aib8,Lys20,Glu22,Val25,Arg26,Glu30]GLP-1(7-33)amide;   N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-[Aib8,Lys20,Glu22,Val25,Arg26,Glu30]GLP-1(7-33)amide;   [Glu22, Arg26]GLP-1(7-33)peptide;   [Glu22,Val25,Arg26]GLP-1(7-32)amide;   N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Arg26)GLP-1(7-33)amide;   N-epsilon31 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Glu22,Val25,Arg26,Lys31)GLP-1(7-33)amide;   N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(DesaminoHis7,Lys20,Glu22,Arg26)GLP-1(7-33)amide;   N-epsilon31 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(DesaminoHis7,Glu22,Arg26,Lys31)GLP-1(7-33)amide;   N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Glu30,Lys31)GLP-1(7-32)amide;   N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8, Lys20,Glu22,Val25,Arg26,Leu27,Nle30,Lys31)GLP-1(7-32)amide;   N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]-[Aib8,Glu22,Val25,Arg26,Lys31]GLP-1-(7-33)amide;   [Desamino His7,Glu22,Arg26]-GLP-1(7-34);   [Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Lys31]GLP-1(7-32)amide;   N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Asp11,Glu18,Glu22,Val25,Arg26,Asp27,Glu30,Lys31]GLP-1(7-33)amide;   [Aib8,Glu22,Val25, Lys31]GLP-1(7-33)-amide; and   N-epsilon31-{2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-N-beta34-(2-(bis-carboxymethylamino)acetyl)[Aib8,Glu22,Val25,Arg26,Lys31,Dap34]GLP-1(7-34)amide.   
     
     
         16 . A pharmaceutical composition comprising a GLP-1 analogue or derivative thereof according to  claim 1  or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient. 
     
     
         17 - 19 . (canceled) 
     
     
         20 . A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 16 .