GIP-GLP-1 dual agonist compounds and methods

A GIP analogue having the general Formula Ib:

• (SEQ ID NO:
• 56) (Ib)
• R1-Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-
• X13-Leu-X15-X16-Ψ-Ala-X19-X20-X21-Phe-X23-X24-Trp-
• Leu-X27-X28-X29-X30-R2
• wherein
• R1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
• X2 is selected from Aib and D-Ala;
• X10 is selected from Tyr and Leu;
• X13 is selected from Ala, Tyr and Aib;
• X15 is selected from Asp and Glu;
• X16 is selected from Glu and Lys;
• X19 is selected from Gln and Ala;
• X20 is selected from Lys and Arg;
• X21 is selected from Ala and Glu;
• X23 is selected from Val and Ile;
• X24 is selected from Asn and Glu;
• X27 is selected from Leu, Glu and Val;
• X28 is selected from Ala, Ser and Arg;
• X29 is selected from Aib, Ala, Glu and Gln;
• X30 is selected from Lys, Gly and Y1, or is absent;
• Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
• 57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
• 58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
• 59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
• 60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
• 61);
• Ψ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z2-Z1, wherein Z2-Z1 is:
• and
• R2 is —NH2 or —OH;
• or a pharmaceutically acceptable salt thereof.

A GIP analog according to the following formula:

• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R2 (SEQ ID NO:
• 34);
• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQGPSSGAPPPS (SEQ ID NO:
• 35)-R2;
• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R2 (SEQ ID NO:
• 36);
• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQ-R2 (SEQ ID NO:
• 156);
• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQ-R2 (SEQ ID NO:
• 157);
• or
• R1—Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQ-R2 (SEQ ID NO:
• 158)
• wherein R1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
• and
• R2 is —NH2 or —OH,
• or a pharmaceutically acceptable salt thereof.