Bifunctional compounds
The application discloses compounds useful in treatment of diabetes, weight loss and/or reduction of cardiovascular risks. The compounds are bi-functional and therefore suitable as a simple treatment for patients that may benefit from treatment with both a GLP-1 receptor agonist and a PCSK9 inhibitor.
1. A compound comprising a GLP-1 analogue and an EGF(A) analogue, wherein
i. said GLP-1 analogue has at most 6 amino acid substitutions compared to GLP-1(7-37) identified by SEQ ID NO: 137 and
ii. said EGF(A) analogue has 1-8 amino acid substitutions compared to the EGF(A) domain of LDL-R (293-332) identified by SEQ ID NO:1, and comprises 301Leu and
wherein the compound is a GLP-1 agonist.
2. The compound according to claim 1 , wherein the compound comprises a fusion polypeptide comprising the GLP-1 analogue and the EGF(A) analogue.
3. The compound according to claim 2 , wherein the GLP-1 analogue is located N-terminally with respect to EGF(A) analogue.
4. The compound according to claim 1 , wherein the GLP-1 analogue comprises one or two Lys residues selected from the group consisting of: 12K, 21K, 23K, 24K, 25K, 26K, 27K, 30K, 31K, 32K, 33K, 34K and 36K.
5. The compound according to claim 1 , wherein the GLP-1 analogue is selected from the group consisting of GLP-1 analogues defined by SEQ ID NOs: 138 to 187.
6. The compound according to claim 1 , wherein the GLP-1 analogue comprises 8Aib.
7. The compound according to claim 1 , wherein the GLP-1 analogue comprises 34R or 34Q.
8. The compound according to claim 1 , wherein GLP-1 analogue comprises 8Aib and 34R.
9. The compound according to claim 1 , wherein the GLP-1 analogue is selected from the group consisting of GLP-1 analogues defined by SEQ ID NOs: 139, 147-154 and 184-186.
10. The compound according to claim 1 , wherein the GLP-1 analogue is defined by SEQ ID NO: 139.
11. The compound according to claim 1 , wherein the EGF(A) analogue comprises 309R.
12. The compound according to claim 1 , wherein the EGF(A) analogue comprises 321D or 321E.
13. The compound according to claim 1 , wherein the EGF(A) analogue comprises 312E, 312D, 312Q or 312R.
14. The compound according to claim 1 , wherein the EGF(A) analogue is selected from the group consisting of EGF(A) analogues defined by SEQ ID NOs: 19, 21, 73, 107, 108, 109, 110, 111, 112, 113 and 114.
15. The compound according to claim 1 , wherein the EGF(A) analogue is defined by SEQ ID NO: 107.
16. The compound according to claim 1 , wherein the EGF(A) analogue is defined by SEQ ID NO: 108.
17. The compound according to claim 2 , wherein the fusion polypeptide comprises a peptide spacer selected from the group of consisting of spacers defined by SEQ ID NOs: 115-136.
18. The compound according to claim 2 , wherein the fusion polypeptide comprises a peptide spacer, wherein the peptide spacer is defined by SEQ ID NO: 116 or SEQ ID NO: 119.
19. The compound according to claim 1 , wherein the compound comprises at least one half-life extending substituent, selected from the group consisting of: substituent #1 defined by Chem 6b,
substituent #2 defined by Chem 7b,
substituent #3 defined by Chem 8b,
substituent #4 defined by Chem 9b,
substituent #5 defined by Chem 10b,
substituent #6 defined by Chem 11b,
substituent #7 defined by Chem 12b,
substituent #8 defined by Chem 13b,
substituent #9 defined by Chem 14b,
substituent #10 defined by Chem 15b,
substituent #11 defined by Chem 16b,
substituent #12 defined by Chem 17b,
substituent #13 defined by Chem 18b,
and substituent #14 defined by Chem 19b,
20. A compound selected from the group consisting of compounds #41, #48, #69 and #306, wherein
compound #41 comprises a fusion peptide defined by SEQ ID NO: 190 consisting of the GLP-1 analogue [8Aib, 34R]GLP-1(7-37) defined by SEQ ID NO: 139, the Spacer defined by SEQ ID NO: 116, and the EGF(A) analogue [301L, 309R, 312E, 321E, 333K]EGF(A) defined by SEQ ID NO: 19 and two substituents defined by Chem 6b
attached to amino acid residues 26K of [8Aib, 34R]GLP-1(7-37) and 333K of [301L, 309R, 312E, 321E, 333K]EGF(A),
compound #48 comprises a fusion peptide defined by SEQ ID NO: 202 consisting of the GLP-1 analogue [8Aib, 34R]GLP-1(7-37) defined by SEQ ID NO: 139, the Spacer defined by SEQ ID NO: 119, and the EGF(A) analogue defined by SEQ ID NO: 108 and one substituent defined by Chem 11b
attached to amino acid 26K of [8Aib, 34R]GLP-1(7-37),
compound #69 comprises a fusion peptide defined by SEQ ID NO: 310 consisting of the GLP-1 analogue [8Aib, 30G, 34R]GLP-1(7-37) defined by SEQ ID NO: 164, the Spacer defined by SEQ ID NO: 116, and the EGF(A) analogue defined by SEQ ID NO: 108 and one substituent defined by Chem 11b
attached to amino acid 26K of [8Aib, 30G, 34R]GLP-1(7-37),
compound #306 comprises a fusion peptide defined by SEQ ID NO: 310 consisting of the GLP-1 analogue [8Aib, 30G, 34R]GLP-1(7-37) defined by SEQ ID NO: 164, the Spacer defined by SEQ ID NO: 116, and the EGF(A) analogue defined by SEQ ID NO: 108 and one substituent defined by Chem 10b
attached to amino acid 26K of [8Aib, 30G, 34R]GLP-1(7-37).
21. A compound of #69, wherein
compound #69 comprises a fusion peptide defined by SEQ ID NO: 310 consisting of the GLP-1 analogue [8Aib, 30G, 34R]GLP-1(7-37) defined by SEQ ID NO: 164, the Spacer defined by SEQ ID NO: 116, and the EGF(A) analogue defined by SEQ ID NO: 108 and one substituent defined by Chem 11b
attached to amino acid 26K of [8Aib, 30G, 34R]GLP-1(7-37).
22. A compound of #306, wherein
compound #306 comprises a fusion peptide defined by SEQ ID NO: 310 consisting of the GLP-1 analogue [8Aib, 30G, 34R]GLP-1(7-37) defined by SEQ ID NO: 164, the Spacer defined by SEQ ID NO: 116, and the EGF(A) analogue defined by SEQ ID NO: 108 and one substituent defined by Chem 10b
attached to amino acid 26K of [8Aib, 30G, 34R]GLP-1(7-37).
23. A compound according to claim 1 , wherein the compound is a GLP-1/EGF(A) compound wherein the GLP-1 analogue is defined by SEQ ID NO: 139 and the EGF(A) analogue is defined by SEQ ID NO: 108.
24. A GLP-1/EGF(A) compound, wherein the compound comprises a fusion peptide defined by SEQ ID NO: 193 and one substituent defined by Chem 6b
attached via Lysine (K) in position 20 of SEQ ID 193 (equal to amino acid 26K of [8Aib, 34R]GLP-1(7-37)).
25. A method of treatment of diabetes, over-weight or a cardiovascular disease comprising administering a pharmaceutically effective dosage of a compound according to claim 1 to a patient in need thereof.