Anti-obesity agents

• US 7,601,691 B2
• Filed: 02/25/2005
• Issued: 10/13/2009
• Est. Priority Date: 05/17/1999
• Status: Expired due to Fees

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem Biotechnologies, Inc. /Old/ (Colabor Group, Inc.)
• Inventors: Huang, Xicai, Thibaudeau, Karen, Robitaille, Martin, Bridon, Dominique P., Milner, Peter G., Leger, Roger
• Primary Examiner(s): Desai; Anand U
• Application Number:
  US11/067,556
• Publication Number:
  US 20050176643A1
• Time in Patent Office: 1,691 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/00 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 Class Codes: C07K 14/57545 Neuropeptide Y
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2319/01 containing a localisation/targetting motif

Abstract

The present invention relates to a compound comprising a PYY peptide or a functional derivative thereof, which is coupled to a reactive group. Such a reactive group is capable of reacting on a blood component so as to form a stable covalent bond therewith. The present invention also relates to a conjugate comprising such a compound which is covalently bonded to a blood component. Moreover, the invention also relates to a method of enhancing, in a patient, the anti-obesity activity of a PYY peptide or functional derivative thereof.

Claims

1. A compound comprising a peptide moiety and a Michael acceptor (MA) moiety, the MA moiety being capable of reacting with an amino group, a hydroxyl group or a thiol group on a blood protein so as to form a stable covalent bond, therewith, wherein the compound is of the formula:

X₁-X₂ Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg X₃ (SEQ ID NO;

22)

wherein

X₁ is ile, ile(N-MA) or ile(N-linking group-MA);

X₂ is lys or lys(N^ε

-linking group-MA);

X₃ is tyr or a tyr derivative of formula

2. The compound of claim 1, wherein X₁ is ile (N-MA) and X₂ is lys.

3. The compound of claim 1, wherein X₁ is ile (N-linking group-MA) and X₂ is lys.

4. The compound of claim 1, wherein X₁ is ile and X₂ is lys(N^ε

-linking group-MA).

5. The compound of any one of claims 1-4, wherein said Michael acceptor is a maleimido-containing group.

6. The compound of claim 5, wherein said maleimido-containing group is maleimidopropionic acid.

7. The compound of any one of claims 1-4, wherein said blood protein is albumin.

8. The compound of any one of claims 1, 3 and 4, wherein said linking group is selected from the group consisting of (2-amino) ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), 2-[2-(2-amino)ethoxy] ethoxy acetic acid (AEEA), AEEA-AEEA, —

NH₂—

(CH₂)_n-COOH where n is an integer from 1 to 20;

one or more alkyl chains (C₁-C₁₀) saturated or unsaturated which optionally comprises oxygen, nitrogen or sulfur atoms motifs, glycine, 3-aminopropionic acid (APA), 8-aminooctanoic acid (OA), 4-aminobenzoic acid (APhA), and combinations thereof.

17. The compound of any one of claims 1-4 wherein X₃ is tyr-CONH₂.

24. The compound of claim 6, wherein said blood protein is albumin.

25. The compound of claim 7, wherein said blood protein is albumin.

27. The compound of claim 17, wherein said blood protein is albumin.

28. The compound of claim 6, wherein X₃ is tyr-CONH₂.

29. The compound of claim 7, wherein X₃ is tyr-CONH₂.

30. The compound of claim 28, wherein the blood protein is albumin.

31. The compound of claim 29, wherein the blood protein is albumin.

32. The compound of claim 27, wherein the Michael acceptor is capable of being covalently linked to a thiol group at amino acid residue 34 (Cys34) on albumin.

36. The compound of claim 1, wherein the blood protein is a recombinant protein.

37. The compound of claim 7, wherein the albumin is a recombinant protein.

9. A conjugate formed by the reaction of a compound with a blood protein under conditions sufficient to form a stable covalent bond therewith, wherein the compound comprises a peptide moiety and a Michael acceptor (MA) moiety, wherein the MA moiety is coupled to an amino group, a hydroxyl group or a thiol group on said blood protein, and wherein the compound is of the formula:

X₁-X₂ Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg X₃ (SEQ ID NO;

22)

wherein

X₁ is ile, ile(N-MA) or ile(N-linking group-MA);

X₂ is lys or lys(N^ε

-linking group-MA);

X₃ is tyr or a tyr derivative of formula

10. The conjugate of claim 9, wherein X₁ is ile(N-MA) and X₂ is lys.

11. The conjugate of claim 9, wherein X₁ is ile(N-linking group-MA) and X₂ is lys.

12. The conjugate of claim 9, wherein X₁ is ile and X₂ is lys(N^ε

-linking group-MA).

13. The conjugate of any one of claims 9-12, wherein said Michael acceptor is a maleimido-containing.

14. The conjugate of claim 13, wherein said maleimido-containing group is maleimidopropionic acid (MPA).

15. The conjugate of any one of claims 9-12, wherein said blood protein is albumin.

16. The conjugate of claim 9, 11, or 12, wherein said linking group is selected from the group consisting of (2-amino) ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), 2-[2-(2-amino)ethoxy] ethoxy acetic acid (AEEA), AEEA-AEEA, —

NH₂—

(CH₂)_n—

COOH where n is an integer from 1 to 20;

one or more alkyl chains (C₁-C₁₀) saturated or unsaturated which optionally comprises oxygen, nitrogen or sulfur atoms motifs, glycine, 3-aminopropionic acid (APA), 8-aminooctanoic acid (OA), 4-aminobenzoic acid (APhA), and combinations thereof.

18. The conjugate of any one of claims 9-12 wherein X₃ is tyr-CONH₂.

19. The conjugate of claim 13, wherein said blood protein is albumin, X₃ is tyr-CONH₂, and said linking group is selected from the group consisting of (2-amino)ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), 2-[2-(2-amino)ethoxy] ethoxy acetic acid (AEEA), AEEA-AEEA, —

NH₂—

(CH₂)_n—

COOH where n is an integer from 1 to 20;

one or more alkyl chains (C₁-C₁₀) saturated or unsaturated which optionally comprises oxygen, nitrogen or sulfur atoms motifs, glycine, 3-aminopropionic acid (APA), 8-aminooxtanoic acid (OA), 4-aminobenzoic acid (APhA), and combinations thereof.

20. The conjugate of claim 14, wherein said blood protein is albumin, X₃ is tyr-CONH₂, and said linking group is selected from the group consisting of (2-amino)ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), 2-[2-(2-amino)ethoxy] ethoxy acetic acid (AEEA), AEEA-AEEA, —

NH₂—

(CH₂)_n—

COOH where n is an integer from 1 to 20;

one or more alkyl chains (C₁-C₁₀) saturated or unsaturated which optionally comprises oxygen, nitrogen or sulfur atoms motifs, glycine, 3-aminopropionic acid (APA), 8-aminooxtanoic acid (OA), 4-aminobenzoic acid (APhA), and combinations thereof.

21. The conjugate of claim 10, wherein said blood protein is albumin, X₃ is tyr-CONH₂, and said Michael acceptor is maleimidopropionic acid (MPA).

22. The conjugate of claim 11, wherein said blood protein is albumin, X₃ is tyr-CONH₂, and said Michael acceptor is maleimidopropionic acid (MPA), and said linking group is 8-aminooctanoic acid (OA).

23. The conjugate of claim 12, wherein said blood protein is albumin, X₃ is tyr-CONH₂, said Michael acceptor is maleimidopropionic acid (MPA), and said linking group is 8-aminooxtanoic acid (OA).

26. The compound of claim 10, wherein the Michael acceptor is capable of being covalently linked to a thiol group at amino acid residue 34 (Cys34) on albumin.

33. The conjugate of claim 13, the blood protein is albumin.

34. The conjugate of claim 14, the blood protein is albumin.

35. The conjugate of claim 15, wherein the Michael acceptor moiety is covalently linked to a thiol group at amino acid residue 34 (Cys34) on albumin.

38. The conjugate of claim 9, wherein the blood protein is a recombinant protein.

39. The conjugate of claim 15, wherein the albumin is a recombinant protein.