GIP-GLP-1 dual agonist compounds and methods

1. A GIP analogue having the general Formula I:

(I)

(SEQ ID NO: 56)

R 1 -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-R 2

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;

X2 is Aib;

X10 is Tyr;

X13 is Ala;

X15 is Asp;

X16 is Lys;

X19 is Gln;

X20 is Arg;

X21 is Ala;

X23 is Val;

X24 is Glu;

X27 is Leu;

X28 is Ala;

X29 is Gln;

X30 is Y1;

Y1 is Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 58);

Ψ is K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3);

and

R 2 is —NH 2 or —OH;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the composition is formulated as a liquid suitable for administration by injection or infusion, or formulated to cause slow release of said GIP analogue.

3. A method of treatment and/or prevention of diabetes or a diabetes related disorder, or obesity or an obesity related disorder, comprising administering to a subject in need thereof a GIP analogue according to claim 1 , or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3 , wherein:

(a) the diabetes related disorder is insulin resistance, glucose intolerance, increased fasting glucose, hypoglycemia, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorder or a combination thereof; or

(b) the diabetes related disorder is atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, or a proinflammatory state; or

(c) the obesity related disorder is obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, or a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, or a combination thereof.

5. The GIP analogue of claim 1 , wherein R1 is H— and R2 is —NH 2 and the GIP analogue has the sequence of:

(SEQ ID NO: 216)

H-Y-Aib-EGTFTSDYSIALDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQKPSSGAPPPS-NH 2 .

6. The method according to claim 4 , wherein:

(a) the bone related disorder is osteoporosis;

(b) the blood fat disorder is high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof.