Glucagon analogues

Abstract

The invention provides materials and methods for promoting weight loss or preventing weight gain without affecting glycemic control. In particular, the invention provides novel glucagon analogue peptides effective in such methods. The peptides may mediate their effect by having increased selectivity for the GLP-1 receptor as compared to human glucagon.

1 . A compound having the formula
   R 1 —X—Z—R 2  
   wherein   R 1  is H, C 1-4  alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;   R 2  is OH or NH 2 ;   X is a peptide which has the formula I:   
       
         
           
                 
               
                   (I) 
                 
                   (SEQ ID NO: 11) 
                 
                   His-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- 
                 
                   Tyr-Leu-Asp-X16-X17-Arg-Ala-X20-Asp-Phe-Ile-Glu- 
                 
                   Trp-Leu-X27-X28-X29  
                 
             
                
                
                
                
                
               
            
           
         
         wherein 
         X2 is selected from Ser and Aib; 
         X16 is selected from Glu and Y; 
         X17 is selected from Arg and Y; 
         X20 is selected from Lys and Y; 
         X27 is selected from Leu and Y; 
         X28 is selected from Ser and Y or absent; 
         X29 is Ala or absent; 
         wherein at least one of X16, X17, X20, X27 and X28 is Y; 
         wherein each residue Y is independently selected from Lys, Cys and Orn; 
         wherein the side chain of at least one amino acid residue Y of X is conjugated to a lipophilic substituent having the formula: 
         (i) Z 1 , wherein Z 1  is a lipophilic moiety conjugated directly to the side chain of Y; or 
         (ii) Z 1 Z 2 , wherein Z 1  is a lipophilic moiety, Z 2  is a spacer, and Z 1  is conjugated to the side chain of Y via Z 2 ; 
         and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  having the sequence 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 12) 
                 
                     
                   HSQGTFTSDYSKYLDERRAKDFIEWLKSA  
                 
                     
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   HSQGTFTSDYSKYLDERRAKDFIEWLLSA  
                 
                     
                     
                 
                     
                   (SEQ ID NO: 14) 
                 
                     
                   HSQGTFTSDYSKYLDERRAKDFIEWLLKA  
                 
                     
                     
                 
                     
                   (SEQ ID NO: 15) 
                 
                     
                   HSQGTFTSDYSKYLDKRRAKDFIEWLLSA  
                 
                     
                     
                 
                     
                   (SEQ ID NO: 16) 
                 
                     
                   HSQGTFTSDYSKYLDEKRAKDFIEWLLSA  
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 17) 
                 
                     
                   H-Aib-QGTFTSDYSKYLDEKRAKDFIEWLLSA. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         3 . A compound according to  claim 1 , wherein said lipophilic substituent is attached to the amino acid residue at position 16, 17, 20, 27 or 28. 
     
     
         4 . A compound according to  claim 1  wherein R 1  is H. 
     
     
         5 . A compound according to  claim 1  wherein R 2  is NH 2 . 
     
     
         6 . A compound according to  claim 1 , having the sequence 
       
         
           
                 
               
                   (SEQ ID NO: 5) 
                 
                   H-HSQGTFTSDYSKYLDERRAKDFIEWL-K(Hexadecanoyl- 
                 
                   isoGlu)-SA-NH 2   
                 
                     
                 
                   (SEQ ID NO: 6) 
                 
                   H-HSQGTFTSDYSKYLDERRA-K(Hexadecanoyl-isoGlu)-  
                 
                   DFIEWLLSA-NH 2   
                 
                     
                 
                   (SEQ ID NO: 7) 
                 
                   H-HSQGTFTSDYSKYLDERRAKDFIEWLL-K(Hexadecanoyl- 
                 
                   isoGlu)-A-NH 2   
                 
                     
                 
                   (SEQ ID NO: 8) 
                 
                   H-HSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)- 
                 
                   RRAKDFIEWLLSA-NH 2   
                 
                     
                 
                   (SEQ ID NO: 9)  
                 
                   H-HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   RAKDFIEWLLSA-NH 2   
                 
                   or 
                 
                   (SEQ ID NO: 10) 
                 
                   H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   RAKDFIEWLLSA-NH 2 . 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . A compound according to  claim 1  wherein one or more of the amino acid side chains in the compound is conjugated to a polymeric moiety. 
     
     
         8 . A compound according to  claim 7  wherein one or more of the amino acid side chains in peptide X is conjugated to a polymeric moiety. 
     
     
         9 . A composition comprising a compound according to  claim 1 , or a salt or derivative thereof, in admixture with a carrier. 
     
     
         10 . A composition according to  claim 9  wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier. 
     
     
         11 . (canceled) 
     
     
         12 . A method of preventing weight gain or promoting weight loss in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         13 . A method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         14 . The method of  claim 12 , wherein the subject has a condition caused or characterised by excess body weight. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to  claim 13  wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension. 
     
     
         17 . The method according to  claim 16 , wherein the agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY receptor agonist or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist. 
     
     
         18 . The method according to  claim 16  wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker. 
     
     
         19 . The method according to  claim 16  wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorbtion inhibitor.