IP Library › Granted Patent US 9,580,487
Granted Patent B2
US 9,580,487 · App. 14/847,938 · Granted Feb 28, 2017

Method of treating stomach or bowel-related disorders by administering glucagon-like-peptide-2 (GLP-2) analogues

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Quick Facts
Patent No.
US 9,580,487
App. No.
14/847,938
Granted
Feb 28, 2017
Kind
B2
Abstract

GLP-2 analogs are disclosed which comprise one of more substitutions as compared to [hGly2]GLP-2 and which improved biological activity in vivo and/or improved chemical stability, e.g., as assessed in in vitro stability assays. More particularly, preferred GLP-2 analogs disclosed herein comprise substitutions at one or more of positions 8, 16, 24 and/or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 (as mentioned in the introduction) and one or more of positions 3, 5, 7, 10 and 11, and/or a deletion of one or more of amino acids 31 to 33 and/or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogs are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy. Also disclosed are methods and kits for selecting a patient from populations suited for treatment with GLP-2 analogs.

Claims (469)

1. A method of treating a patient having a stomach or bowel-related disorder, said method comprising administering an effective amount of a glucagon-like peptide-2 (GLP-2) analog to said patient, wherein said analog is selected from the group consisting of:

(SEQ ID NO: 1) (Compound 1809)

H-HGEGTFSDELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 2) (Compound 1810)

H-HGEGTFSDELATILDALAARIFIAWLIATKKKKKKK-NH 2 ,

(SEQ ID NO: 3) (Compound 1811)

H-HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 4) (Compound 1812)

H-HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 5) (Compound 1813)

H-HGDGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 6) (Compound 1814)

H-HGDGSFSDELATILDNLAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 7) (Compound 1815)

H-HGEGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 8) (Compound 1818)

H-HGDGSFSSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 9) (Compound 1819)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 10) (Compound 1820)

H-HGDGSFTSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 11) (Compound 1821)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 12) (Compound 1822)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 13) (Compound 1823)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 14) (Compound 1824)

H-HGDGSFTDELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 15) (Compound 1825)

H-HGDGSFSSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 17) (Compound 1827)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 18) (Compound 1828)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 19) (Compound 1829)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 20) (Compound 1830)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 21) (Compound 1831)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 22) (Compound 1832)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 23) (Compound 1833)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 24) (Compound 1834)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 25) (Compound 1835)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 26) (Compound 1836)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 27) (Compound 1839)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 ,

(SEQ ID NO: 28) (Compound 1840)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 29) (Compound 1841)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 30) (Compound 1842)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 31) (Compound 1843)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 32) (Compound 1844)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 33) (Compound 1845)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 35) (Compound 1847)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 38) (Compound 1850)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 39) (Compound 1851)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 40) (Compound 1852)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 41) (Compound 1853)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 42) (Compound 1854)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITD-NH 2

(SEQ ID NO: 43) (Compound 1855)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 44) (Compound 1856)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 47) (Compound 1859)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 48) (Compound 1860)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 49) (Compound 1861)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the GLP-2 analogue is selected from the group consisting of:

(SEQ ID NO: 24) (Compound 1834)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 35) (Compound 1847)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 43) (Compound 1855)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein the GLP-2 analogue is selected from the group consisting of:

(SEQ ID NO: 17) (Compound 1827)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 32) (Compound 1844)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 33) (Compound 1845)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 38) (Compound 1850)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 39) (Compound 1851)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 40) (Compound 1852)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 43) (Compound 1850)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 47) (Compound 1859)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein the GLP-2 analogue is

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

or a pharmaceutically acceptable salt thereof.

5. A method of treating a patient having a stomach or bowel-related disorder, said method comprising administering an effective amount of a glucagon-like peptide-2 (GLP-2) analogue to said patient, wherein the GLP-2 analogue is selected from the group consisting of:

(SEQ ID NO: 20) (Compound 1830)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 21) (Compound 1831)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 25) (Compound 1835)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 26) (Compound 1836)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 27) (Compound 1839)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 ,

(SEQ ID NO: 28) (Compound 1840)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 29) (Compound 1841)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 ,

and

(SEQ ID NO: 31) (Compound 1843)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 ;

or a pharmaceutically acceptable salt thereof.

6. A method of treating a patient having a stomach or bowel-related disorder, said method comprising administering an effective amount of a glucagon-like peptide-2 GLP-2 analog to said patient, wherein said analog is selected from the group consisting of:

(SEQ ID NO: 1) (Compound 1809)

H-HGEGTFSDELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 2) (Compound 1810)

H-HGEGTFSDELATILDALAARIFIAWLIATKKKKKKK-NH 2 ,

(SEQ ID NO: 3) (Compound 1811)

H-HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 4) (Compound 1812)

H-HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 5) (Compound 1813)

H-HGDGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 6) (Compound 1814)

H-HGDGSFSDELATILDNLAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 7) (Compound 1815)

H-HGEGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 8) (Compound 1818)

H-HGDGSFSSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 9) (Compound 1819)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 10) (Compound 1820)

H-HGDGSFTSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 11) (Compound 1821)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 12) (Compound 1822)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 13) (Compound 1823)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 14) (Compound 1824)

H-HGDGSFTDELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 15) (Compound 1825)

H-HGDGSFSSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 17) (Compound 1827)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 18) (Compound 1828)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 19) (Compound 1829)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 20) (Compound 1830)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 21) (Compound 1831)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 22) (Compound 1832)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 23) (Compound 1833)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 24) (Compound 1834)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 25) (Compound 1835)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 26) (Compound 1836)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 27) (Compound 1839)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 ,

(SEQ ID NO: 28) (Compound 1840)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 29) (Compound 1841)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 30) (Compound 1842)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 31) (Compound 1843)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 32) (Compound 1844)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 33) (Compound 1845)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 35) (Compound 1847)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 38) (Compound 1850)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 39) (Compound 1851)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 40) (Compound 1852)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 41) (Compound 1853)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 42) (Compound 1854)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 43) (Compound 1855)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 44) (Compound 1856)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 47) (Compound 1859)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 48) (Compound 1860)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 49) (Compound 1861)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof, and

wherein said stomach or bowel-related disorder is selected from the group consisting of ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small intestine damage, and short bowel syndrome.

7. The method of claim 6 , wherein said stomach or bowel-related disorder is ulcers.

8. The method of claim 6 , wherein said stomach or bowel-related disorder is a digestion disorder.

9. The method of claim 6 , wherein said stomach or bowel-related disorder is a malabsorption syndrome.

10. The method of claim 6 , wherein said stomach or bowel-related disorder is a cul-de-sac syndrome.

11. The method of claim 6 , wherein said stomach or bowel-related disorder is celiac sprue.

12. The method of claim 6 , wherein said stomach or bowel-related disorder is tropical sprue.

13. The method of claim 6 , wherein said stomach or bowel-related disorder is hypogammaglobulinemic sprue.

14. The method of claim 6 , wherein said stomach or bowel-related disorder is enteritis or regional enteritis (Crohn's disease).

15. The method of claim 6 , wherein said stomach or bowel-related disorder is ulcerative colitis.

16. The method of claim 6 , wherein said stomach or bowel-related disorder is small intestine damage.

17. The method of claim 16 , wherein said stomach or bowel-related disorder is small intestinal damage due to toxic or other chemotherapeutic agents.

18. The method of claim 6 , wherein said stomach or bowel-related disorder is short bowel syndrome.

19. A method of treating a patient having short-gut syndrome, said method comprising administering an effective amount of a glucagon-like peptide-2 (GLP-2) analog to said patient, wherein said analog is selected from the group consisting of:

(SEQ ID NO: 1) (Compound 1809)

H-HGEGTFSDELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 2) (Compound 1810)

H-HGEGTFSDELATILDALAARIFIAWLIATKKKKKKK-NH 2 ,

(SEQ ID NO: 3) (Compound 1811)

H-HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 4) (Compound 1812)

H-HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 5) (Compound 1813)

H-HGDGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 6) (Compound 1814)

H-HGDGSFSDELATILDNLAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 7) (Compound 1815)

H-HGEGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 8) (Compound 1818)

H-HGDGSFSSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 9) (Compound 1819)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 10) (Compound 1820)

H-HGDGSFTSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 11) (Compound 1821)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 12) (Compound 1822)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 13) (Compound 1823)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 14) (Compound 1824)

H-HGDGSFTDELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 15) (Compound 1825)

H-HGDGSFSSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 17) (Compound 1827)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 18) (Compound 1828)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 19) (Compound 1829)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 20) (Compound 1830)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 21) (Compound 1831)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 22) (Compound 1832)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 23) (Compound 1833)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 24) (Compound 1834)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 25) (Compound 1835)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 26) (Compound 1836)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 27) (Compound 1839)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 ,

(SEQ ID NO: 28) (Compound 1840)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 29) (Compound 1841)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 30) (Compound 1842)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 31) (Compound 1843)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 32) (Compound 1844)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 33) (Compound 1845)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 35) (Compound 1847)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 38) (Compound 1850)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 39) (Compound 1851)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 40) (Compound 1852)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 41) (Compound 1853)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 42) (Compound 1854)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 43) (Compound 1855)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 44) (Compound 1856)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 47) (Compound 1859)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 48) (Compound 1860)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 49) (Compound 1861)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof.

20. A method of treating a patient having a stomach or bowel-related disorder, said method comprising administering an effective amount of a glucagon-like peptide-2 (GLP-2) analog to said patient, wherein said analog is selected from the group consisting of:

(SEQ ID NO: 1) (Compound 1809)

H-HGEGTFSDELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 2) (Compound 1810)

H-HGEGTFSDELATILDALAARIFIAWLIATKKKKKKK-NH 2 ,

(SEQ ID NO: 3) (Compound 1811)

H-HGDGSPSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 4) (Compound 1812)

H-HGEGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 5) (Compound 1813)

H-HGDGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 6) (Compound 1814)

H-HGDGSFSDELATILDNLAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 7) (Compound 1815)

H-HGEGSFSDELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 8) (Compound 1818)

H-HGDGSFSSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 9) (Compound 1819)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 10) (Compound 1820)

H-HGDGSFTSELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 11) (Compound 1821)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 12) (Compound 1822)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 13) (Compound 1823)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 14) (Compound 1824)

H-HGDGSFTDELATILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 15) (Compound 1825)

H-HGDGSFSSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 17) (Compound 1827)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 18) (Compound 1828)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 19) (Compound 1829)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTKKKKKKK-NH 2 ,

(SEQ ID NO: 20) (Compound 1830)

H-HGDGSFSDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 21) (Compound 1831)

H-HGDGSFTDELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 22) (Compound 1832)

H-HGDGSFTSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 23) (Compound 1833)

H-HGDGSFSSELSTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 24) (Compound 1834)

H-HGDGSFTSELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 25) (Compound 1835)

H-HGDGSFSDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 26) (Compound 1836)

H-HGDGSFTDELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 27) (Compound 1839)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITDKKKKKK-NH 2 ,

(SEQ ID NO: 28) (Compound 1840)

H-HGDGSFSDELATILDNLAARDFIAWLIQTKITD-NH 2 ,

(SEQ ID NO: 29) (Compound 1841)

H-HGDGSFSDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 30) (Compound 1842)

H-HGDGSFTSELKTILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 31) (Compound 1843)

H-HGDGSFTDELATILDNLAARDFIAWLIQTK-NH 2 ,

(SEQ ID NO: 32) (Compound 1844)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 33) (Compound 1845)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 35) (Compound 1847)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 36) (Compound 1848)

H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 37) (Compound 1849)

H-HGEGSFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 38) (Compound 1850)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 39) (Compound 1851)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 40) (Compound 1852)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITDKKKKKK-NH 2 ,

(SEQ ID NO: 41) (Compound 1853)

H-HGEGTFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 42) (Compound 1854)

H-HGEGTFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 43) (Compound 1855)

H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 44) (Compound 1856)

H-HGEGSFSDELSTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 45) (Compound 1857)

H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 46) (Compound 1858)

H-HGEGSFSSELATILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 47) (Compound 1859)

H-HGEGSFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

(SEQ ID NO: 48) (Compound 1860)

H-HGEGTFSDELKTILDALAARDFIAWLIATKITD-NH 2 ,

and

(SEQ ID NO: 49) (Compound 1861)

H-HGEGTFSSELKTILDALAARDFIAWLIATKITD-NH 2 ;

or a pharmaceutically acceptable salt thereof, and

wherein said stomach or bowel-related disorder is selected from the group consisting of radiation enteritis, infectious enteritis, and post-infectious enteritis.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded May 17, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063672/0342 →
RELEASE OF SECURITY INTEREST Recorded May 11, 2023
From: ZOOLANDER SA LLC
To: ZEALAND PHARMA A/S
Reel/Frame 063624/0547 →
PATENT SECURITY AGREEMENT Recorded Dec 27, 2021
From: ZEALAND PHARMA A/S
To: ZOOLANDER SA LLC
Reel/Frame 058593/0261 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 30, 2016
From: LARSEN, BJARNE DUE; PETERSEN, YVETTE MIATA
To: ZEALAND PHARMA A/S
Reel/Frame 039914/0987 →