α4β7 thioether peptide dimer antagonists
The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.
1. A peptide comprising the sequence:
(SEQ ID NO: 270)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-
Phe(4-tBu)-(β-homo-Glu)-(D-Lys).
2. The peptide of claim 1 , comprising a thioether bond between the 2-methylbenzoyl and the Pen.
3. The peptide of claim 1 , further comprising a linker moiety.
4. The peptide of claim 3 , wherein the linker moiety is bound to the D-Lys amino acid.
5. The peptide of claim 4 , wherein the linker moiety is diglycolic acid (DIG).
6. The peptide of claim 1 , comprising a C-terminal OH.
7. The peptide of claim 1 , comprising a C-terminal NH 2 .
8. The peptide of claim 1 , comprising a thioether bond between the 2-methylbenzoyl and the Pen, and a linker moiety bound to the D-Lys amino acid.
9. A peptide dimer compound comprising two peptides, each peptide comprising the sequence:
(SEQ ID NO: 270)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-
Phe(4-tBu)-(β-homo-Glu)-(D-Lys),
or a pharmaceutically acceptable salt thereof,
wherein the two peptides are linked by a linker moiety.
10. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein the linker moiety is bound to the D-Lys amino acids of the two peptides.
11. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein the linker moiety is diglycolic acid (DIG).
12. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen.
13. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides comprises a C-terminal NH 2 .
14. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides comprises a C-terminal OH.
15. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, and wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides.
16. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides consists of the sequence:
(SEQ ID NO: 223)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe
(4-tBu)-(β-homo-Glu)-(D-Lys)-OH,
wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).
17. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein each of the two peptides consists of the sequence:
(SEQ ID NO: 222)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-
Phe(4-tBu)-(β-homo-Glu)-(D-Lys)-NH 2 ,
wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).
18. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.
19. A pharmaceutical composition comprising the peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9 , and a pharmaceutically acceptable excipient, carrier or diluent.
20. The pharmaceutical composition of claim 19 , wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).
21. The pharmaceutical composition of claim 20 , wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.
22. The pharmaceutical composition of claim 19 , wherein each of the two peptides consists of the sequence:
(SEQ ID NO: 222)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-
Phe(4-tBu)-(β-homo-Glu)-(D-Lys)-NH 2 ,
wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).
23. The pharmaceutical composition of claim 19 , wherein each of the two peptides consists of the sequence:
(SEQ ID NO: 223)
2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-
Phe(4-tBu)-(β-homo-Glu)-(D-Lys)-OH,
wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).
24. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition comprises an enteric coating.
25. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition is formulated for oral delivery.
26. The pharmaceutical composition of claim 25 , further comprising an enteric coating.
27. The pharmaceutical composition of claim 26 , wherein the enteric coating releases the pharmaceutical composition within a subject's lower gastrointestinal system.
28. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, the method comprising providing to the subject an effective amount of the pharmaceutical composition of claim 19 .
29. The method of claim 28 , wherein the IBD is ulcerative colitis.
30. The method of claim 28 , wherein the IBD is Crohn's disease.
31. The method of claim 28 , wherein the peptide molecule is administered orally.