OXYNTOMODULIN ANALOGUES AND THEIR EFFECTS ON FEEDING BEHAVIOUR

• US 20090298757A1
• Filed: 06/13/2006
• Published: 12/03/2009
• Est. Priority Date: 06/13/2005
• Status: Abandoned Application

• Current Assignee: Imperial Innovations Limited (Imperial College London)
• Original Assignee: Imperial Innovations Limited (Imperial College London)
• Inventors: Ghatei, Mohammad Ali, Bloom, Stephen Robert
• Application Number:
  US11/917,503
• Publication Number:
  US 20090298757A1
• Time in Patent Office: Days
• 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: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Compounds of the invention are novel peptide analogues of oxyntomodulin (oxm) in which one or more amino acids of the oxm sequence have been changed. Changing amino acids 15-24 of oxm to either amino acids 968-977 of the α-latrotoxin peptide (and variations thereof) or amino acids 15-24 of exendin-4 (and variations thereof), or combinations of sequences from these sources, and/or changing amino acids 27-33 of oxm to amino acids 27-33 of exendin-4, and/or the addition of amino acids to the C-terminus of the peptide, results in a series of analogues of oxm that demonstrate the oxm like activity of reducing food intake, and with certain embodiments a greater ability to decrease food intake.

Claims

1. A compound having the general Formula (I):

Z-X—

S1 

 

(I)

in which;

X is oxyntomodulin (“

oxm”

) amino acid residues 4-14; and

Z is an amino acid sequence of three amino acid residues;

wherein S1 is an amino acid sequence corresponding to line A (SEQ ID NO;

1) or an amino acid sequence corresponding to line A in which m amino acids of said line A are substituted by m corresponding amino acids from residues 15 to 37 in line B (SEQ ID NO;

     2), and t further amino acid residues of line A are substituted by t corresponding amino acid residues from residues 15 to 24 of line R, in which line A, line B and line R (SEQ ID NO;

     145) are as follows;

2. A compound according to claim 1, in which t=0.

3. A compound according to claim 1, in which t=5 or more.

4. A compound according to claim 1, in which Z is an amino acid sequence of two amino acid residues followed by Gln, Asp or Glu.

5. A compound according to claim 1, in which the amino acid replacements from line B comprises at least one sequential group of at least three amino acids.

6. A compound according to claim 1, in which the replaced amino acids comprises a sequential group of not more than twelve amino acids.

7. A compound according to claim 1, having a Formula selected from the following group:

8. A compound according to claim 1, in which the compound is of general Formula (II):

Z-X—

S2-Y 

 

(II)

in which X and Z are as defined in claim 1;

Y is oxm25-37; and

wherein S2 is an amino acid sequence corresponding to line C (SEQ ID NO;

     3) in which n amino acids of said line C are substituted by n corresponding amino acids from line D (SEQ ID NO;

     4) and u further amino acids of line C are substituted by u corresponding amino acids from line S (SEQ ID NO;

     145), in which line C, line D and Line S are as follows;

9. A compound according to claim 8 in which u=0.

10. A compound according to claim 8 in which u=5 or more.

11. A compound according to claim 8, in which the amino acid substitution from line D comprises at least three amino acids.

12. A compound according to claim 8, in which the amino acid substitution from line D comprises at least one sequential group of two or more amino acids.

13. A compound according to claim 8, in which the amino acid substitution from line D comprises a sequential group of at least four amino acids.

14. A compound according to claim 8, in which the amino acid substitution from line D comprises a sequential group of not more than ten amino acids.

15. A compound according to claim 13, in which the sequential group has from 5 to 10 amino acids.

16. A compound according to claim 13, in which the sequential group has from 6 to 10 amino acids.

17. A compound according to claim 13, in which the sequential group has from 7 to 10 amino acids.

18. A compound according to claim 8, in which the amino acid substitution from line S comprises at least three amino acids.

19. A compound according to claim 8, in which the amino acid substitution from line S comprises at least one sequential group of two or more amino acids.

20. A compound according to claim 8, in which the amino acid substitution from line S comprises a sequential group of at least four amino acids.

21. A compound according to claim 8, in which the amino acid substitution from line S comprises a sequential group of not more than ten amino acids.

22. A compound according to claim 20, in which the sequential group has from 5 to 10 amino acids.

23. A compound according claim 20, in which the sequential group has from 6 to 10 amino acids.

24. A compound according to claim 20, in which the sequential group has from 7 to 10 amino acids.

25. A compound according to claim 8, which is a of sequence selected from the group consisting of:

26. A compound according to claim 1, in which the compound is of general Formula (III):

Z-X′

—

S3-Y′

 

 

(III)

in which X′

is oxm-4-26;

Z is as defined in claim 1;

Y′

is oxm34-37; and

wherein S3 is an amino acid sequence corresponding to line E (SEQ ID NO;

     5) in which p amino acids of said line E are substituted by p corresponding amino acids from line F (SEQ ID NO;

     6), in which line E and line F are as follows;

27. A compound according to claim 26, in which the substituted amino acids comprise at least three amino acids.

28. A compound according to claim 26, in which the substituted amino acids comprise at least one sequential group of two or more amino acids.

29. A compound according to claim 28, in which the substituted amino acids comprise a sequential group of at least three amino acids.

30. A compound according claim 26, in which the substituted amino acids comprise a sequential group of not more than seven amino acids.

31. A compound according to claim 30, in which the sequential group has from 3 to 7 amino acids.

32. A compound according to claim 31, in which the sequential group has four amino acids.

33. A compound according to claim 28, in which the sequential group has from 4 to 7 amino acids.

34. A compound according to claim 26 which is a of sequence selected from the group consisting of:

44. A compound according to claim 1, in which Z represents His-Ser-Gln.

45. A compound according to claim 1, in which Z represents a moiety A-B-C in which A is an amino acid other than L-histidine, B is L-alanine or L-serine and C is L-aspartate, L-glutamate or L-glutamine.

46. A compound according to claim 45, in which Z represents D-His-Ala-Gln;

D-His-Ala-Glu;

D-His-Ala-Asp;

D-His-Ser-Gln;

D-His-Ser-Glu;

or D-His-Ser-Asp.

47. A compound according to claim 1, in which:

X is oxm amino acid residues 4-14;

wherein S1 is an amino acid sequence corresponding to line A (SEQ ID NO;

1) or an amino acid sequence corresponding to line A in which m amino acids of said line A are substituted by m corresponding amino acids from residues 15 to 37 in line B (SEQ ID NO;

     2), and t further amino acid residues of line A are substituted by t corresponding amino acid residues from residues 15 to 24 of line R, in which line A, line B and line R (SEQ ID NO;

     145) are as follows;

48. A compound according to claim 47, in which A¹ is a D-amino acid.

49. A compound according to claim 48, in which the D-amino acid is D-histidine.

50. A compound according to claim 47, in which A¹ is D-histidine, A² is L-alanine and A³ is L-glutamate or L-aspartate.

51. A compound according to claim 47 in which S1 includes the entirety of line A.

52. A compound according to claim 1, in which the terminal residue is an amide group.

53. A compound according to claim 1, having an extension moiety consisting of at least two amino acids.

54. A compound according to claim 53, having one of the following extension moieties -Ala(38)-Ala(39);

-Lys(38);

-Ala(38)-Ala(39)-Lys(40);

-Ala(38)-Ala(39)-Lys(40)-Lys(41);

-Ala(38)-Ala(39)-Glu(40)-Glu(41)-Lys(42).

55. A compound according to claim 53, having the extension moiety -Pro(38)-Ser(39).

57. A compound as claimed in claim 1, wherein at least one of the amino acid residues has an alkyl or acyl side chain.

58. A compound as claimed in claim 57, wherein said alkyl or acyl side chain or side chains are selected from the group comprising hexadecyl, dodecyl, palmitoyl and lauroyl.

59. A compound as claimed in claim 57 having an acyl side chain attached to the amino acid residue at one or more of positions 30, 33, 38, 40 and 42.

60. A compound as claimed in claim 57 having a formula selected from the following group:

61. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further amino acid from positions 4 to 37 is substituted by an alternative amino acid.

62. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further two amino acids from positions 4 to 37 are substituted by alternative amino acids.

63. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further three amino acids from positions 4 to 37 are substituted by alternative amino acids.

64. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further four amino acids from positions 4 to 37 are substituted by alternative amino acids.

65. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further five amino acids from positions 4 to 37 are substituted by alternative amino acids.

66. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, F, F, R, and S above a further six amino acids from positions 4 to 37 are substituted by alternative amino acids.

67. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further seven amino acids from positions 4 to 37 are substituted by alternative amino acids.

68. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further eight amino acids from positions 4 to 37 are substituted by alternative amino acids.

69. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, E, F, R, and S above a further nine amino acids from positions 4 to 37 are substituted by alternative amino acids.

70. A compound according to claim 1, wherein independently of the sequence substitutions defined by reference to lines A, B, C, D, B, F, R, and S above a further ten or more amino acids from positions 4 to 37 are substituted by alternative amino acids.

71. A variant compound according to claim 61, wherein said variant compound retains at least some of the activity of the corresponding non-variant compound.

72. A variant compound according to claim 61, wherein said variant compound exhibits either enhanced appetite suppression activity, a greater potency, a more therapeutically useful profile, or a lower clearance rate, relative to the corresponding non-variant compound.

73. A variant compound according to claim 61, wherein at least one of said further amino acid substitutions is a conservative amino acid substitution according to the following table:

74. A variant compound according to claim 73, wherein all of said further amino acid substitutions are conservative amino acid substitutions according to the table given in claim 66.

84. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers.

85. A method of treating or preventing obesity or diabetes or other co-morbidities of obesity in a subject in need thereof comprising administering to the subject a compound of claim 1.

86. A method of reducing appetite in a subject, reducing food intake in a subject, or reducing calorie intake in a subject, reducing the body weight in a subject, reducing body weight gain in a subject, or increasing energy expenditure in a subject comprising administering to the subject a compound of claim 1.

87. The method of claim 85, wherein the subject is overweight.

88. The method of claim 85, wherein the subject is obese.

89. The method of claim 85, wherein the subject is diabetic.

90. The method of claim 85, wherein the compound is administered peripherally.

91. The method of claim 85 wherein the compound is administered subcutaneously, intravenously, intramuscularly, intranasally, transdermally, transmucosally, orally or sublingually.

35. A compound of the general formula (IV):

Z-X—

S2-Trp-Leu-S3-Y′

 

 

(IV)

wherein,

X is oxm amino acid residues 4-14; and

Z is an amino acid sequence of three amino acid residues or an amino acid sequence of two amino acid residues followed by Gln, Asp or Glu,

wherein S2 is an amino acid sequence corresponding to line C (SEQ ID NO;

     3) in which n amino acids of said line C are substituted by n corresponding amino acids from line D (SEQ ID NO;

     4) and u further amino acids of line C are substituted by u corresponding amino acids from line S (SEQ ID NO;

     145) in which line C, line D and Line S are as follows;

36. A compound according to claim 35, which is selected from the group consisting:

37. A compound of the general Formula (V):

Z-X—

S4-S5-E 

 

(V)

in which;

X is oxm 4-14,

Z is an amino acid sequence of three amino acid residues or an amino acid sequence of two amino acid residues followed by Gln, Asp or Glu,

S4 represents a ten amino acid sequence consisting of from 0 to 10 correspondingly positioned amino acids from the sequence Asp Ser Arg Arg Ala Gln Asp Phe Val Gln (SEQ ID NO;

     35), from 1 to 10 correspondingly positioned amino acids from the sequence Glu Glu Glu Ala Val Arg Leu Phe Ile Glu (SEQ ID NO;

     4), optionally from 0 to 9 correspondingly positioned amino acids from the sequence Arg Ile Glu Ile Val Lys Tyr Phe Val Gly (SE ID NO;

     145),

and from 0 to 5 amino acids that differ in identity from the correspondingly positioned amino acids in SEQ ID NO;

4, SEQ ID NO;

145, and SEQ ID NO;

35,

S5 represents oxm25-37 or represents oxm25-37 in which at least one residue at positions 27 to 33 has been substituted by one or more correspondingly numbered residues from the sequence Lys(27) Asn(28) Gly(29) Gly(30) Pro(31) Ser(32) Ser(33) (SEQ ID NO;

     24); and

E represents an optional extension moiety comprising one or more amino acid residues;

a variant or derivative thereof;

or a salt or solvate thereof.

38. A compound according to claim 37, in which S4 contains at least three correspondingly positioned amino acids from either SEQ ID NO:

4 or SEQ ID NO;

145.

39. A compound according to claim 37, in which S4 includes at least one amino acid differing in identity to the correspondingly positioned amino acids in SEQ ID NO:

4, SEQ ID NO;

145 and SEQ ID NO;

35.

40. A compound according to claim 37, in which S4 contains at least six correspondingly positioned amino acids from SEQ ID NO:

4 or SEQ ID NO;

145, and at least one amino acid differing in identity to the correspondingly positioned amino acids in SEQ ID NO;

4, SEQ ID NO;

145 and SEQ ID NO;

35.

41. A compound according to claim 37, in which S4 is made up of nine correspondingly positioned amino acids from SEQ ID NO:

4 or SEQ ID NO;

145, and at least one amino acid differing in identity to the correspondingly positioned amino acids in SEQ ID NO;

4, SEQ ID NO;

145, and SEQ ID NO;

35.

42. A compound according to claim 37, in which S5 represents:

-Trp-Leu-S3-Y′

in which Y′

is oxm34-37 and S3 is an amino acid sequence corresponding to line E (SEQ ID NO;

     5) in which p amino acids of said line E are substituted by p corresponding amino acids from line F (SEQ ID NO;

     6), in which line E and line F are as follows;

43. A compound according to claim 42, which has one of the following sequences:

56. A compound having the formula oxm-Ala(38) Ala(39).

75. A compound having the general Formula (VI):

76. A compound as claimed in claim 75, wherein X is one amino acid.

77. A compound as claimed in claim 75, wherein X is two amino acids.

78. A compound as claimed in claim 75, wherein X is three amino acids.

79. A compound as claimed in claim 75, wherein X is four amino acids.

80. A compound as claimed in claim 75, wherein X is five amino acids.

81. A compound as claimed in claim 75, wherein X is Ala-Y wherein Y is any one or more amino acids or is absent.

82. A compound as claimed in claim 75 which has a sequence selected from the following group:

83. A compound having the general Formula (VII):

92-96. -96. (canceled)