Analogues of PYY

Patent metadata

Field	Value
Publication number	US-12060402-B2
Application number	US-202217868559-A
Country	US
Kind code	B2
Filing date	Jul 19, 2022
Priority date	Dec 4, 2017
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

Analogues of PYY differing from native human PYY by substitution of Ser23 with Ala23, Glu23, Lys23, Gln23 or AIB23. Further optional features include substitutions at further positions, loss of the Tyr1 residue of native human PYY and amidation of the C-terminus. Suitable for use as pharmaceuticals for treating and preventing disorders, in particular diabetes and obesity.

First claim

The invention claimed is:

1. A method of treating obesity, reducing appetite, reducing food intake, or reducing calorie intake in a subject, comprising:
administering to a subject in need thereof a therapeutically effective amount of
a) an analogue of PYY which differs from the sequence of native human PYY (SEQ ID NO: 1) in the following respects:
i) Ser23 is substituted with Ala23, Glu23, or Aib23,
ii) Asn18 is substituted with Leu18, Aib18 or Ala18, and
iii) the analogue of PYY further differs from the sequence of native human PYY in at least one of the following respects:
Tyr1 is absent,
Glu10 is substituted with Lys10 or Gln10,
Asp11 is substituted with Gly11,
Arg19 is substituted with His19,
Tyr27 is substituted with Phe27,
Leu30 is substituted with His30, and
Val31 is substituted with Leu31,

wherein
Lys4 is not substituted, and
the C-terminal residue optionally terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H); or

b) a derivative of the analogue, wherein the derivative is selected from the group consisting of amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, PEGylation, and fusion to another peptide or to a protein to form a fusion protein, or
c) a salt or solvate of the analogue or the derivative of the analogue.

2. The method as claimed in claim 1 , wherein the C-terminal residue terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H).

3. The method as claimed in claim 1 , wherein Ser23 is substituted with Ala23.

4. The method of claim 1 ,
wherein the analogue of PYY is selected from the group consisting of Y1372 (SEQ ID NO: 20), Y1419 (SEQ ID NO: 23), Y1421 (SEQ ID NO: 24), Y1518 (SEQ ID NO: 32), Y1528 (SEQ ID NO: 33), Y1558 (SEQ ID NO: 35), Y1568 (SEQ ID NO: 36), and Y1579 (SEQ ID NO: 41).

5. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1419 (SEQ ID NO: 23).

6. The method as claimed in claim 1 , wherein
Glu10 is unsubstituted,
Asn18 is substituted with Leu18, and
Ser23 is substituted with Ala23.

7. The method as claimed in claim 1 , wherein
Asn18 is substituted with Leu18, and
Val31 is unsubstituted.

8. The method as claimed in claim 1 , wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the analogue of PYY or derivative thereof together with a pharmaceutically acceptable carrier, and optionally a further therapeutic agent.

9. The method as claimed in claim 8 , wherein the further therapeutic agent is selected from an analogue of GLP-1, an analogue of glucagon, and a derivative of either thereof.

10. The method as claimed in claim 8 , wherein the pharmaceutical composition further comprises Zn 2+ ions.

11. The method as claimed in claim 1 , wherein the subject is overweight or obese.

12. The method as claimed in claim 1 , wherein the therapeutically effective amount of an analogue of PYY or a derivative thereof is administered parenterally.

13. The method as claimed in claim 1 , wherein the therapeutically effective amount of an analogue of PYY or a derivative thereof is administered subcutaneously.

14. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1372 (SEQ ID NO: 20).

15. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1421 (SEQ ID NO: 24).

16. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1518 (SEQ ID NO: 32).

17. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1528 (SEQ ID NO: 33).

18. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1558 (SEQ ID NO: 35).

19. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1568 (SEQ ID NO: 36).

20. The method as claimed in claim 4 , wherein the analogue of PYY is compound Y1579 (SEQ ID NO: 41).

21. A method of treating diabetes in a subject, comprising:
administering to a subject with diabetes a therapeutically effective amount of
a) an analogue of PYY which differs from the sequence of native human PYY (SEQ ID NO: 1) in the following respects:
i) Ser23 is substituted with Ala23, Glu23, or Aib23,
ii) Asn18 is substituted with Leu18, Aib18 or Ala18, and
iii) the analogue of PYY further differs from the sequence of native human PYY in at least one of the following respects:
Tyr1 is absent,
Glu10 is substituted with Lys10 or Gln10,
Asp11 is substituted with Gly11,
Arg19 is substituted with His19,
Tyr27 is substituted with Phe27,
Leu30 is substituted with His30, and
Val31 is substituted with Leu31,

wherein
Lys4 is not substituted, and
the C-terminal residue optionally terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H); or

b) a derivative of the analogue, wherein the derivative is selected from the group consisting of amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, PEGylation, and fusion to another peptide or to a protein to form a fusion protein, or
c) a salt or solvate of the analogue or the derivative of the analogue.

22. The method as claimed in claim 21 , wherein the C-terminal residue terminates in a primary amide group (—C(O)NH 2 ) in place of a carboxylic acid group (—CO 2 H).

23. The method as claimed in claim 21 , wherein Ser23 is substituted with Ala23.

24. The method of claim 21 , wherein the analogue of PYY is selected from the group consisting of Y1372 (SEQ ID NO: 20), Y1419 (SEQ ID NO: 23), Y1421 (SEQ ID NO: 24), Y1518 (SEQ ID NO: 32), Y1528 (SEQ ID NO: 33), Y1558 (SEQ ID NO: 35), Y1568 (SEQ ID NO: 36), and Y1579 (SEQ ID NO: 41).

25. The method as claimed in claim 24 , wherein the analogue of PYY is compound Y1419 (SEQ ID NO: 23).

26. The method as claimed in claim 21 , wherein
Glu10 is unsubstituted,
Asn18 is substituted with Leu18, and
Ser23 is substituted with Ala23.

27. The method as claimed in claim 21 , wherein
Asn18 is substituted with Leu18, and
Val31 is unsubstituted.

28. The method as claimed in claim 21 wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the analogue of PYY or derivative thereof together with a pharmaceutically acceptable carrier, and optionally a further therapeutic agent.

29. The method as claimed in claim 28 , wherein the further therapeutic agent is selected from an analogue of GLP-1, an analogue of glucagon, or a derivative of either thereof.

30. The method as claimed in claim 28 , wherein the pharmaceutical composition further comprises Zn 2+ ions.

31. The method as claimed in claim 21 , wherein the subject is overweight or obese.

32. The method as claimed in claim 21 , wherein the therapeutically effective amount of an analogue of PYY or a derivative thereof is administered parenterally.

33. The method as claimed in claim 32 , wherein the therapeutically effective amount of an analogue of PYY or a derivative thereof is administered subcutaneously.

34. The method as claimed in claim 24 , wherein the analogue of PYY is compound Y1372 (SEQ ID NO: 20).

Assignees

• Ip2Ipo Innovations Ltd

Inventors

• Bloom Stephen Robert

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K9/0029

  Parenteral nutrition; Parenteral nutrition compositions as drug carriers · CPC title

• A61K38/26

  Glucagons · CPC title

• A61K38/2271

  Neuropeptide Y · CPC title

• C07K14/57545 Primary

  Neuropeptide Y · CPC title