Glucagon-glp-1-gip triple agonist compounds

Abstract

The present invention relates to compounds which have agonist activity at the glucagon, GIP and GLP-1 receptors, and to their use in the treatment of metabolic disorders.

1 . A glucagon-GLP-1-GIP triple agonist compound having the general formula I: 
       
         
           
                 
               
                   (I) 
                 
                   R 1 -Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12- 
                 
                     
                 
                   X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24- 
                 
                     
                 
                   Trp-Leu-X27-X28-X29-X30-Y1-R 2   
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein 
         R 1  is H—, C 1-4  alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu; 
         X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c; 
         X10 is Tyr or Leu; 
         X12 is Lys, Ile or ψ; 
         X13 is Ala, Tyr or Aib; 
         X15 is Asp or Glu; 
         X16 is Ser, Glu, Lys or ψ; 
         X17 is Lys or ψ; 
         X19 is Gln or Ala; 
         X20 is Lys, His, Arg or ψ; 
         X21 is Ala, Asp or Glu; 
         X23 is Val or lie; 
         X24 is Asn, Glu or ψ; 
         X27 is Leu, Glu or Val; 
         X28 is Ala, Ser, Arg or ψ; 
         X29 is Aib, Ala, Gln or Lys; 
         X30 is Lys, Gly, or is absent; 
       
       
         
           
                 
               
                   Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly- 
                 
                     
                 
                   Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Lys-Pro-Ser-Ser- 
                 
                     
                 
                   Gly-Ala-Pro-Pro-Pro-Ser, Lys-Pro-Ser-Ser-Gly-Ala- 
                 
                     
                 
                   Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser 
                 
                   or 
                 
                     
                 
                   Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, or is absent; 
                 
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent; 
         and 
         R 2  is —NH 2  or —OH; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein W is present at one of positions X12, X16 or X17. 
     
     
         3 . A compound according to  claim 1  or  claim 2  wherein the compound contains only one residue ψ. 
     
     
         4 . A compound according to any one of  claims 1  to  3  wherein the compound possesses one or more of the following sets of residues:
 K12 and K12 and Y13; I12 and Y13; K12 and A13; I12 and A13; or ψ12 and Y13; 
 D15 and S16; D15 and E16; E15 and K16; D15 and ψ16; E15 and S16; or E15 and ψ16; 
 A19, H20, and D21; A19, K20, and D21; A19, R20, and D21; Q19, K20, and E21; A19, K20, and E21; or Q19, R20, and A21; 
 I23 and E24; V23 and E24; or V23 and N24; 
 L27, R28, and A29; L27, S28, and A29; L27, A28, and Q29; E27, S28, and A29; or V27, A28, and Aib29; 
 E15 and K17; 
 E15 and ψ17; 
 E15, ψ17, and Q19; 
 Q19 and E24; 
 E16, ψ17, and Q19; or 
 K16, ψ17, and Q19. 
 
     
     
         5 . A compound according to  claim 4  further comprising:
 Aib2, Ser2 or Ac4c2; and/or 
 Tyr10; or 
 Leu10. 
 
     
     
         6 . A compound according to any one of the preceding claims wherein positions 1 to 29 have the sequence: 
       
         
           
                 
               
                   YSQGTFTSDYSKYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   YSQGTFTSDYSKYLDΨKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSΨAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEΨKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSΨYLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDLSIALEKΨAQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDEΨAAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKDFVEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKEFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKΨAQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALDKΨAQRAFVNWLVA-Aib; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDEΨAAKEFIEWLESA; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIALEKΨAQRAFVEWLLAQ; 
                 
                   or 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDKΨAQRAFVEWLLAQ. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . A compound according to  claim 1  which differs at up to 4 positions from any of the sequences listed in  claim 6 . 
     
     
         8 . A compound according to  claim 7  which differs at up to 4 positions from one of the sequences: 
       
         
           
                 
               
                   Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; 
                 
                   and 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQ. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . A compound according to  claim 1  wherein the peptide backbone of Formula I has the sequence: 
       
         
           
                 
               
                   YSQGTFTSDYSKYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   YSQGTFTSDYSKYLDΨKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLESKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDKKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSΨAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKALDSKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLESKAAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAKDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEKAAKDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSKAARDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAQKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLEKKAQKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKALDEKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEΨKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSΨYLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVNWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDLSIALEKΨAQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDEΨAAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKDFVEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAKEFIEWLESA ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSKAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDSΨAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEKΨAQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALDKΨAQRAFVNWLVA-Aib-KPSSGAPPPS; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDEΨAAKEFIEWLESA; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIALEKΨAQRAFVEWLLAQK; 
                 
                   or 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDKΨAQRAFVEWLLAQGPSSGAPPPS. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         10 . A compound according to  claim 1  wherein the peptide backbone of Formula I has a sequence which differs at up to 5 positions from one of the sequences shown in in  claim 10 . 
     
     
         11 . A compound according to  claim 10  which differs at up to 5 positions from one of the sequences: 
       
         
           
                 
               
                   Y-Aib-QGTFTSDYSIYLEKΨAAKEFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDEΨAAHDFVEWLLSA; 
                 
                   or 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEKΨAQRAFVEWLLAQK. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . A compound according to any one of the preceding claims wherein W is a residue of Lys in which the side chain is conjugated to a lipophilic substituent. 
     
     
         13 . A compound according to any one of the preceding claims wherein the lipophilic substituent has the formula —Z 1  or —Z 2 —Z 1  wherein:
 —Z 1  is a fatty chain having at a terminus a connection —X— to ψ or to Z 2 ; 
 wherein 
 —X— is a bond, —CO—, —SO—, or —SO 2 —; 
 and, optionally, Z 1  has a polar group at the end of the chain distal from connection —X—, said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; 
 and wherein —Z 2 —, if present, is a spacer of formula: 
 
       
         
           
           
               
               
           
         
         connecting Z 1  to ψ; 
         wherein: 
         each Y is independently —NH, —NR, —S or —O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ; 
         each X is independently a bond, CO—, SO—, or SO 2 —; 
         with the proviso that when Y is —S, the X to which it is bound is a bond; 
         each V is independently a bivalent organic moiety linking Y and X; 
         and n is 1-10. 
       
     
     
         14 . A compound according to  claim 13  wherein the lipophilic substituent has the formula —Z 2 —Z 1 . 
     
     
         15 . A compound according to  claim 12  or  claim 14  wherein Z 1  is A-B-alkylene-CO— wherein A is H or —COOH and B is a bond. 
     
     
         16 . A compound according to  claim 15  wherein Z 1  is A-B—C 16-20 alkylene-(CO)—. 
     
     
         17 . A compound according to any one of  claims 13  to  16  wherein Z 1  is:
 hexadecanoyl; 17-carboxy-heptadecanoyl [HOOC—(CH 2 ) 16 —(CO)—]; 
 19-carboxy-nonadecanoyl [HOOC—(CH 2 ) 18 —(CO)—]; 
 Octadecanoyl [H 3 C—(CH 2 ) 16 —(CO)—]; or 
 Eicosanoyl [H 3 C—(CH 2 ) 18 —(CO)—]. 
 
     
     
         18 . A compound according to any one of  claims 13  to  17  wherein Z 2  comprises a residue selected from isoGlu or Dapa. 
     
     
         19 . A compound according to  claim 13  wherein —Z 1  or —Z 2 —Z 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound according to  claim 1  wherein positions 1 to 29 have the sequence: 
       
         
           
                 
               
                   YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)- 
                 
                   KAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)- 
                 
                   KAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)- 
                 
                   YLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3-Peg3)- 
                 
                   AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQ; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFVEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVNWLVA-Aib; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-Peg3)- 
                 
                   AQRAFVNWLVA-Aib; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALDK-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ; 
                 
                   or 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQ. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         21 . A compound according to  claim 1  wherein the peptide backbone of Formula I has the sequence: 
       
         
           
                 
               
                   YSQGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)- 
                 
                   KAAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K(Hexadecanoyl-isoGlu)- 
                 
                   KAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)- 
                 
                   YLEKKAAKEFVEWLLSA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKEFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AAKEFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLEK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFVEWLLSAGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu)-AQRAFVEWLLAQGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLD-K(eicosanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQGPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEK-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALEK-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDLSIALE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLAQK; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFVEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)- 
                 
                   AAKDFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDE-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)- 
                 
                   AAHDFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIYLE-K([17-carboxy-heptadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLRA; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-isoGlu-Peg3- 
                 
                   Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALD-K(Octadecanoyl-Dapa-Peg3-Peg3)- 
                 
                   AQRAFVNWLVA-Aib-KPSSGAPPPS; 
                 
                     
                 
                   Y-Aib-QGTFTSDYSIALDK-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVNWLVA-Aib-KPSSGAPPPS; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AAKEFIEWLESA; 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIALE-K([19-carboxy-nonadecanoyl]- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQK; 
                 
                   or 
                 
                     
                 
                   Y-Ac4c-QGTFTSDYSIYLDK-K(19-carboxy-heptadecanoyl- 
                 
                   isoGlu-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         22 . A nucleic acid encoding a peptide having the sequence of Formula I. 
     
     
         23 . An expression construct comprising a nucleic acid according to  claim 22 . 
     
     
         24 . A host cell comprising a nucleic acid according to  22  or an expression construct according to  claim 23  and capable of expressing, and optionally secreting, the peptide. 
     
     
         25 . A pharmaceutical composition comprising a triple agonist compound according to any one of  claims 1  to  21 , or a pharmaceutically acceptable salt or solvate thereof, in admixture with a carrier. 
     
     
         26 . A pharmaceutical composition according to  claim 25  formulated as a liquid suitable for administration by injection or infusion, or formulated to cause slow release of said triple agonist compound. 
     
     
         27 . A triple agonist compound according to any one of  claims 1  to  21 , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of medical treatment. 
     
     
         28 . A triple agonist compound according to any one of  claims 1  to  21 , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment and/or prevention of a metabolic disorder. 
     
     
         29 . A triple agonist compound for use according to  claim 28  wherein the metabolic disorder is diabetes or a diabetes related disorder, or obesity or an obesity related disorder. 
     
     
         30 . A triple agonist compound for use according to  claim 29  wherein the diabetes related disorder is insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorder or a combination thereof. 
     
     
         31 . A GIP analogue or pharmaceutically acceptable salt or solvate thereof for use according to  claim 30  wherein the diabetes-related disorder is osteoporosis, including increased risk of bone fracture. 
     
     
         32 . A triple agonist compound for use according to  claim 29  wherein the diabetes related disorder is atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke; or is a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, or a proinflammatory state. 
     
     
         33 . A triple agonist compound for use according to  claim 32  wherein the blood fat disorder is high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof. 
     
     
         34 . A triple agonist compound for use according to  claim 32  wherein the prothrombotic state comprises high fibrinogen levels in the blood or high plasminogen activator inhibitor-1 levels in the blood. 
     
     
         35 . A triple agonist compound for use according to  claim 32  wherein the proinflammatory state comprises an elevated C-reactive protein level in the blood. 
     
     
         36 . A triple agonist compound for use according to  claim 32  wherein the obesity related disorder is obesity linked inflammation, obesity linked gallbladder disease or obesity induced sleep apnea, or may be associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof.