Acylated glp-1/glp-2 dual agonists

A method of prophylaxis or treatment of

• (a) malabsorption, ulcers, short-bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, mucositis induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, low grade inflammation, metabolic endotoxemia, necrotising enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease, or gastrointestinal side-effects of inflammatory conditions in a subject in need thereof, or
• (b) obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes, metabolic syndrome or hypertension in a subject in need thereof;
• the method comprising administering a glucagon-like-peptide 1/glucagon-like-peptide 2 (GLP-1/GLP-2) dual agonist, or pharmaceutically acceptable salt thereof, to the subject, wherein the GLP-1/GLP-2 dual agonist is represented by the formula:
• R1—X*—U—R2,
• wherein:
• R1 is hydrogen (Hy), C1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
• R2 is NH2 or OH;
• X* is a peptide of formula I:
• (I)
• (SEQ ID NO:
• 3)
• H-X2-EG-X5-F-X7-X8-E-X10-X11-TIL-X15-X16-X17-A-
• X19-X20-X21-FI-X24-WL-X27-X28-X29-KIT-X33,
• wherein:
• X2 is Aib or G;
• X5 is T or S;
• X7 is T or S;
• X8 is S, E or D;
• X10 is L, M, V or ψ;
• X11 is A, N or S;
• X15 is D or E;
• X16 is G, E, A or ψ;
• X17 is Q, E, K, L or ψ;
• X19 is A, V or S;
• X20 is R, K or ψ;
• X21 is D, L or E;
• X24 is A, N or S;
• X27 is I, Q, K, H or Y;
• X28 is Q, E, A, H, Y, L, K, R or S;
• X29 is H, Y or Q;
• X33 is D or E;
• U is absent or a sequence of 1-15 residues, each, independently, selected from K, k, E, A, T, I, L and ψ;
• the molecule contains one and only one ψ, wherein ψ is a residue of K, k, R, Orn, Dap or Dab in which the side chain is conjugated to a substituent having the formula Z1— or Z1—Z2—, wherein
• Z1— is CH3—(CH2)10-22—(CO)— or HOOC—(CH2)10-22—(CO)—;
• and
• Z2— is selected from —ZS1—, —ZS1—ZS2—, —ZS2—ZS1—, —ZS2—, —ZS3—, —ZS1—ZS3—, —ZS2—ZS3—, —ZS3—ZS1—, —ZS3—ZS2—, —ZS1—ZS2—ZS3—, —ZS1—ZS3—ZS2—, —ZS2—ZS1—ZS3—, —ZS2—ZS3—ZS1—, —ZS3—ZS1—ZS2—, —ZS3—ZS2—ZS1—, or —ZS2—ZS3—ZS2—;
• wherein
• ZS1 is isoGlu, β-Ala, isoLys, or 4-aminobutanoyl;
• ZS2 is -(Peg3)m-, wherein m is 1, 2, or 3;
• and
• ZS3 is a peptide sequence of 1-6 amino acid residues independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F and G;
• and wherein at least one of X5 and X7 is T.