Acylated GLP-1/GLP-2 dual agonists
A compound having agonist activity at the GLP-1 (glucagon-like-peptide 1) and GLP-2 (glucagon-like peptide 2) receptors, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt or solvate thereof in admixture with a pharmaceutically acceptable carrier, an excipient or a vehicle are provided. The compound can be used, inter alia, in the prophylaxis or treatment of intestinal damage and dysfunction, regulation of body weight, and prophylaxis or treatment of metabolic dysfunction.
1. A dual agonist represented by the formula:
R 1 —X*—R 2 ,
wherein:
R 1 is hydrogen (Hy), C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
R 2 is NH 2 or OH;
X* is a peptide H[Aib]EGSFTSELATILDψQAARDFIAWLIQHKITD (SEQ ID NO: 38);
ψ is an L or D Lys residue whose side chain is conjugated to a substituent of formula Z 1 —Z 2 — and Z 1 —Z 2 — is [17-carboxy-heptadecanoyl]-isoGlu-, or a pharmaceutically acceptable salt thereof.
2. The dual agonist according to claim 1 , wherein X* consists of the sequence:
(SEQ ID NO: 85)
H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIQHKITD;
wherein K* indicates an L lysine residue in which the side chain is conjugated to the substituent Z 1 —Z 2 —, or a pharmaceutically acceptable salt thereof.
3. The dual agonist according to claim 2 , which is:
(SEQ ID NO: 200)
Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-
heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH,
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising the dual agonist or pharmaceutically acceptable salt thereof according to claim 1 , in admixture with a pharmaceutically acceptable carrier, an excipient or a vehicle.
5. A pharmaceutical composition comprising the dual agonist or pharmaceutically acceptable salt thereof according to claim 3 , in admixture with a pharmaceutically acceptable carrier, an excipient or a vehicle.