Glucagon receptor agonists

Abstract

The present invention relates to compounds with an extended duration of action at the glucagon receptor as compared to native glucagon. Specifically provided are glucagon receptor agonists with modifications to the structure of native glucagon introduced to selectively agonize the glucagon receptor over an extended period of time.

1 - 15 . (canceled) 
     
     
         16 . A glucagon receptor agonist compound comprising the formula:
   YX 1 QGTFX 2 SDYSKYLDX 3 KKAX 4 EFVX 5 WLLEX 6 X 7      
       wherein
 X 1  is Aib; 
 X 2  is T or L; 
 X 3  is Aib; 
 X 4  is K which is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) a —CO—(CH 2 ) b —CO 2 H, wherein a is 1 or 2 and b is 14 to 24; 
 X 5  is E or A; 
 X 6  is Tor E; 
 X 7  is either absent, or is a peptide selected from the group consisting of GPSSGAPPPS and GPSSG; 
 and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A glucagon receptor agonist comprising the formula consisting of:
   YX 1 QGTFX 2 SDYSKYLDX 3 KKAX 4 EFVX 5 WLLEX 6 X 7      
       wherein
 X 1  is Aib; 
 X 2  is T or L; 
 X 3  is Aib; 
 X 4  is K which is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) a —CO—(CH 2 ) b —CO 2 H, wherein a is 1 or 2 and b is 14 to 24; 
 X 5  is E or A; 
 X 6  is T or E; 
 X 7  is either absent, or is a peptide selected from the group consisting of GPSSGAPPPS and GPSSG; 
 and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A glucagon receptor agonist compound consisting of the formula:
   YX 1 QGTFX 2 SDYSKYLDX 3 KKAX 4 EFVX 5 WLLEX 6 X 7      
       wherein
 X 1  is Aib; 
 X 2  is T or L; 
 X 3  is Aib; 
 X 4  is K which is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) a —CO—(CH 2 ) b —CO 2 H, wherein a is 1 or 2 and b is 14 to 24; 
 X 5  is E or A; 
 X 6  is T or E; 
 X 7  is either absent, or is a peptide selected from the group consisting of GPSSGAPPPS and GPSSG; 
 and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The glucagon receptor agonist of  claim 16  wherein X 2  is T. 
     
     
         20 . The glucagon receptor agonist of any of  claim 16  wherein X 5  is E. 
     
     
         21 . The glucagon receptor agonist of any of  claim 16  wherein X 6  is T. 
     
     
         22 . The glucagon receptor agonist of any of  claim 16  wherein X 7  is GPSSGAPPPS. 
     
     
         23 . The glucagon receptor agonist of any of  claim 16  wherein b is 16 to 18. 
     
     
         24 . The glucagon receptor agonist of  claim 16  wherein: X 2  is T; a is 2; b is 18; X 5  is E; X 6  is T; X 7  is GPSSGAPPPS; and wherein the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 7). 
     
     
         25 . The glucagon receptor agonist of  claim 16  wherein: X2 is L; a is 2; b is 16; X 5  is E; X 6  is T; and X 7  is GPSSGAPPPS; and wherein the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 8). 
     
     
         26 . The glucagon receptor agonist of  claim 16  wherein: X 2  is T; a is 2; b is 16; X 5  is E; X 6  is T; and X 7  is GPSSG; and wherein the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 9). 
     
     
         27 . The glucagon receptor agonist of  claim 16  wherein: X 2  is T; a is 2; b is 18; X 5  is E; X 6  is T; and X 7  is GPSSG; and wherein the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 10). 
     
     
         28 . The glucagon receptor agonist of  claim 16  wherein: X 2  is T; a is 1; b is 16; X 5  is A; X 6  is E; and X 7  is absent (SEQ ID NO: 11). 
     
     
         29 . The glucagon receptor agonist of  claim 16  wherein: X 2  is T; a is 1; b is 18; X 5  is A; X 6  is E; and X 7  is absent (SEQ ID NO: 12). 
     
     
         30 . A method of treating a disease selected from the group consisting of T2DM, obesity, fatty liver disease, NASH, dyslipidernia, metabolic syndrome, hyperinsulinemia and nighttime hypoglycemia, comprising administering to a patient need thereof, an effective amount of the glucagon receptor agonist of  claim 16 . 
     
     
         31 . A pharmaceutical composition comprising the glucagon receptor agonist of  claim 16  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         32 . The glucagon receptor agonist of  claim 16 , wherein the activity of the glucagon receptor agonist at the glucagon receptor is at least 100-fold higher than the potency of the glucagon receptor agonist at the GLP-1 receptor. 
     
     
         33 . A method of inducing non-therapeutic weight-loss comprising administration of an effective amount of a glucagon receptor agonist of  claim 16 .