Inotropic and diuretic effects of exendin and GLP-1

• US 6,703,359 B1
• Filed: 09/22/2000
• Issued: 03/09/2004
• Est. Priority Date: 02/13/1998
• Status: Expired due to Fees

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Prickett, Kathryn, Vine, Will, Beeley, Nigel R. A.
• Primary Examiner(s): Lankford, Jr., Leon B.
• Application Number:
  US09/622,105
• Time in Patent Office: 1,264 Days
• Field of Search: 514/2, 514/866, 530/324
• US Class Current: 514/15.4
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 13/12 of the kidneys

Abstract

Methods for increasing urine flow are disclosed, comprising administration of an effective amount of GLP-1, an exendin, or an exendin or GLP-1 agonist. Methods for increasing urinary sodium excretion and decreasing urinary potassium concentration are also disclosed. The methods are useful for treating conditions or disorders associated with toxic hypervolemia,such as renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension. The present invention also relates to methods for inducing an inotropic response comprising administration of an effective amount of GLP-1, an exendin, or an exendin or GLP-1 agonist. These methods are useful for treating conditions or disorders that can be alleviated by an increase in cardiac contractility such as congestive heart failure. Pharmaceutical compositions for use in the methods of the invention are also disclosed.

Claims

1. A method for increasing urine flow in an individual in need thereof comprising administering an amount of an exendin or an exendin agonist effective to increase urine flow.

2. The method of claim 1, wherein said increase in urine flow is accompanied by an increase in sodium excretion in said individual.

3. The method of claim 1, wherein said increase in urine flow does not increase urinary potassium concentration in said individual.

14. The method according to any of claims 1, 4, 5, 8, 9, 12, or 13, wherein said exendin is exendin-3 [SEQ ID NO. 1].

15. The method according to any of claims 1, 4, 5, 8, 9, 12, or 13, wherein said exendin is exendin-4 [SEQ ID NO. 2].

16. The method according to any of claims 1, 4, 5, 8, 9, 12 or 13, wherein said exendin agonist is a peptide compound of the formula [SEQ. ID. NO. 4]:

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁;

wherein

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₅ is Ala or Thr;

Xaa₆ is Ala, Phe, Tyr or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Asp or Glu;

Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

Xaa₁₁ is Ala or Ser;

Xaa₁₂ is Ala or Lys;

Xaa₁₃ is Ala or Gin;

Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

Xaa₁₅ is Ala or Glu;

Xaa₁₆ is Ala or Glu;

Xaa₁₇ is Ala or Glu;

Xaa₁₉ is Ala or Val;

Xaa₂₀ is Ala or Arg;

Xaa₂₁ is Ala or Leu;

Xaa₂₂ is Phe, Tyr or naphthylalanine;

Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₂₄ is Ala, Glu or Asp;

Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

Xaa₂₆ is Ala or Leu;

Xaa₂₇ is Ala or Lys;

Xaa₂₈ is Ala or Asn;

Z₁ is —

OH,

—

NH₂,

Gly-Z₂,

Gly Gly-Z₂,

Gly Gly Xaa₃₁-Z₂,

Gly Gly Xaa₃₁ Ser-Z₂,

Gly Gly Xaa₃₁ Ser Ser-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂, or

Gly Gly Xaa31 Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈ Xaa₃₉-Z₂;

wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;

Xaa₃₉ is Ser, Thr or Tyr; and

Z₂ is —

OH or —

NH₂; and

pharmaceutically acceptable salts thereof;

provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇, and Xaa₂₈ are Ala; and

provided also that the compound is not exendin-3 [SEQ ID NO. 1] or exendin-4 [SEQ ID NO. 2].

17. The method according to any of claims 1, 4, 5, 8, 9, 12, or 13, wherein said exendin or exendin agonist is administered peripherally.

18. The method according to claim 17, wherein said exendin or exendin agonist is administered subcutaneously.

19. The method of claim 17, wherein said peripheral administration is selected from the group consisting of buccal, nasal, pulmonary, oral, intravenous, intraocular, rectal, and transdermal administration.

4. A method of decreasing the concentration of potassium in the urine of an individual in need thereof comprising administering to said individual an amount of an exendin or an exendin agonist effective to decrease the concentration of potassium in the urine.

5. A method of alleviating a condition or disorder associated with toxic hypervolemia in an individual, comprising administering to said individual a therapeutically effective amount of an exendin or an exendin agonist.

6. The method of claim 5, wherein the condition or disorder is rental failure.

7. The method of claim 5, wherein said condition or disorder is hypertension.

20. The method of claim 5, wherein the condition or disorder is congestive heart failure.

21. The method of claim 5, wherein the condition or disorder is nephrotic syndrome.

22. The method of claim 5, wherein the condition or disorder is pulmonary edema.

23. The method of claim 5, wherein the condition or disorder is cirrhosis.

8. A method of inducing rapid diuresis in an individual in need of diuresis comprising administering to said individual an amount of an exendin or an exendin agonist effective to induce diuresis.

9. A method of preparing an individual for a surgical procedure comprising administering to said individual a therapeutically effective amount of an exendin or an exendin agonist.

10. The method of claim 9, wherein said surgical procedure is selected from the group consisting of ocular surgical procedures and neurosurgical procedures.

11. The method of claim 9, wherein said exendin or exendin agonist is administered to said individual before said surgical procedure.

12. A method of increasing renal plasma flow and glomerular filtration rate in an individual in need thereof comprising administering to said individual an amount of an exendin or an exendin agonist effective to increase renal plasma flow and glomerular filtration rate.

13. A method of treating pre-eclampsia or eclampsia of pregnancy in an individual having pre-eclampsia or eclampsia, comprising administering to said individual a therapeutically effective amount of an exendin or an exendin agonist.

24. A method for increasing cardiac contractility in an individual in need thereof comprising administering an amount of an exendin or an exendin agonist effective to increase cardiac contractility.

27. The method according to claim 24 or claim 25 wherein said exendin is exendin-3 [SEQ ID NO. 1].

28. The method according to claim 24 or claim 25 wherein said exendin is exendin-4 [SEQ ID NO. 2].

29. The method according to claim 24 or 25 wherein said exendin agonist is a peptide compound of the formula [SEQ. ID. NO. 4]:

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁;

wherein

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₅ is Ala or Thr;

Xaa₆ is Ala, Phe, Tyr or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Asp or Glu;

Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

Xaa₁₁ is Ala or Ser;

Xaa₁₂ is Ala or Lys;

Xaa₁₃ is Ala or Gln;

Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

Xaa₁₅ is Ala or Glu;

Xaa₁₆ is Ala or Glu;

Xaa₁₇ is Ala or Glu;

Xaa₁₉ is Ala or Val;

Xaa₂₀ is Ala or Arg;

Xaa₂₁ is Ala or Leu;

Xaa₂₂ is Phe, Tyr or naphthylalanine;

Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₂₄ is Ala, Glu or Asp;

Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

Xaa₂₆ is Ala or Leu;

Xaa₂₇ is Ala or Lys;

Xaa₂₈ is Ala or Asn;

Z₁ is —

OH,

—

NH₂,

Gly-Z₂,

Gly Gly-Z₂,

Gly Gly Xaa₃₁-Z₂,

Gly Gly Xaa₃₁ Ser-Z₂,

Gly Gly Xaa₃₁ Ser Ser-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂,

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂, or

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈ Xaa₃₉-Z₂;

wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;

Xaa₃₉ is Ser, Thr or Tyr; and

Z₂ is —

OH or —

NH₂; and

pharmaceutically acceptable salts thereof;

provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀. Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇, and Xaa₂₈ are Ala; and

provided also that the compound is not exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ ID NO. 2].

30. The method according to claim 24 or claim 25 wherein said exendin or exendin agonist is administered peripherally.

31. The method according to claim 30 wherein said peripheral administration is selected from the group consisting of buccal, nasal, pulmonary, oral, intraocular, rectal, and transdermal administration.

32. The method according to claim 24 or claim 25 wherein said exendin or exendin agonist is administered intravenously.

25. A method for treating a condition or disorder that can be alleviated by increasing cardiac contractility in an individual having said condition or disorder comprising administering an amount of an exendin or an exendin agonist effective to increase cardiac contractility.

26. The method according to claim 25 wherein said condition or disorder is congestive heart failure.

33. The method according to claim 25 wherein the condition or disorder is pulmonary edema.

34. The method according to claim 25 wherein the condition or disorder is systemic edema.

35. The method according to claim 25 wherein the condition or disorder is renal failure.

36. A method of increasing urine flow in an individual in need thereof comprising administering a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist in an amount effective to increase urine flow.

37. A method of decreasing the concentration of potassium in the urine of an individual in need thereof comprising administering a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist in an amount effective to decrease the concentration of potassium in the urine.

38. A method of inducing diuresis in an individual in need thereof comprising administering a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist in an amount effective to induce diuresis.

39. A method of increasing cardiac contractility in an individual in need thereof comprising administering a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist in an amount effective to increase cardiac contractility.

40. A method of alleviating a condition or disorder associated with toxic hypervolemia in an individual having such a condition, comprising administering a therapeutically effective amount of a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist.

41. A method of treating pre-eclampsia or eclampsia of pregnancy in a subject in need thereof, comprising administering a therapeutically effective amount of a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist.

42. A method of treating a condition or disorder that can be alleviated by increasing cardiac contractility in a subject having such a condition, comprising administering a therapeutically effective amount of a compound selected from the group consisting of an exendin, an exendin agonist, a GLP-1, and a GLP-1 agonist.