Novel Glucagon Analogues

Abstract

The present invention relates to novel glucagon peptides, to the use of said glucagon peptides in therapy, to methods of treatment comprising administration of said glucagon peptides to patients in need thereof, and to the use of said glucagon peptides in the manufacture of medicaments. The glucagon peptides of the present invention are of particular interest in relation to the treatment of hyperglycemia, diabetes and obesity, as well as a variety of diseases or conditions associated with hyperglycemia, diabetes and obesity.

1 . A glucagon peptide comprising:
 SEQ ID NO: 1, wherein the following substitutions are present: X 24  is Lys, X 3  is His, X 15  is Glu or X 16  is Ala, Ile, Phe, Arg, Thr, Val, Leu, Glu, Trp, or Tyr, and an amino acid substitution in at least one position selected from the group consisting of X 9 , X 17 , X 20 , and X 30 ; and   a substituent comprising three or more negatively charged moieties, wherein one of the said negatively charged moieties is distal of a lipophilic moiety and where the substituent is attached at the side chain nitrogen of Lys in position 24;   or a pharmaceutically acceptable salt, ester, amide, acid or prodrug thereof.   
     
     
         2 . The glucagon peptide according to  claim 1 , wherein the glucagon peptide comprises an amino acid substitution in position X 9 . 
     
     
         3 . The glucagon peptide according to  claim 1 , wherein the glucagon peptide comprises an amino acid substitution in position X 17 . 
     
     
         4 . The glucagon peptide according to  claim 1 , wherein the glucagon peptide comprises an amino acid substitution in position X 20 . 
     
     
         5 . The glucagon peptide according to  claim 1 , wherein the glucagon peptide comprises an amino acid substitution in position X 30 . 
     
     
         6 . A method for treating atherosclerosis, comprising administering to a patient in need thereof an effective amount of a glucagon peptide in combination with exendin-4; wherein the glucagon peptide comprises SEQ ID NO: 1, wherein (i) X 24  is Lys, (ii) X 3  is His, (iii) X 15  is Glu, (iv) X 16  is selected from the group consisting of Ala, Ile, Phe, Arg, Thr, Val, Leu, Glu, Trp, and Tyr, and (v) an amino acid substitution in at least one position selected from the group consisting of X 9 , X 17 , X 20 , and X 30 ; and
 a substituent comprising three or more negatively charged moieties, wherein one of the said negatively charged moieties is distal of a lipophilic moiety and where the substituent is attached at the side chain nitrogen of Lys in position 24,   or a pharmaceutically acceptable salt, ester, amide, acid or prodrug thereof.   
     
     
         7 . The method according to  claim 6 , wherein the glucagon peptide comprises an amino acid substitution in position X 9 . 
     
     
         8 . The method according to  claim 6 , wherein the glucagon peptide comprises an amino acid substitution in position X 17 . 
     
     
         9 . The method according to  claim 6 , wherein the glucagon peptide comprises an amino acid substitution in position X 20 . 
     
     
         10 . The method according to  claim 6 , wherein the glucagon peptide comprises an amino acid substitution in position X 30 .