Methods for regulating gastrointestinal motility

• US 6,858,576 B1
• Filed: 08/08/1997
• Issued: 02/22/2005
• Est. Priority Date: 08/08/1996
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Beeley, Nigel Robert Arnold, Prickett, Kathryn S., Gedulin, Bronislava
• Primary Examiner(s): Canella, Karen A.
• Application Number:
  US08/908,867
• Time in Patent Office: 2,755 Days
• Field of Search: 514/2, 514/12, 514/21, 514/3, 530/300, 530/308, 424/9.1, 424/9.3
• US Class Current: 514/6.9
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Methods for reducing gastric motility and delaying gastric emptying for therapeutic and diagnostic purposes are disclosed which comprise administration of an effective amount of an exendin or an exendin agonist. Methods for treating conditions associated with elevated, inappropriate, or undesired post-prandial blood glucose levels are disclosed which comprise administration of an effective amount of an exendin or an exendin agonist alone or in conjunction with other anti-gastric emptying agents.

Claims

1. A method of reducing gastric motility in a subject in need thereof comprising administering to said subject an amount of an exendin effective for reducing gastric motility.

3. The method according to claim 1 or 2 wherein said exendin is exendin-3.

4. The method according to claim 1 or 2 wherein said exendin is exendin-4.

5. The method according to claim 1 or 2 wherein said subject is undergoing a gastrointestinal diagnostic procedure.

6. The method according to claim 5 wherein said gastrointestinal diagnostic procedure is a radiological examination.

7. The method according to claim 6 wherein said gastric gastrointestinal diagnostic procedure is magnetic resonance imaging.

8. The method according to claim 1 or 2 wherein said subject is suffering from a gastrointestinal disorder.

2. A method of delaying gastric emptying in a subject in need thereof comprising administering to said subject an amount of an exendin effective for delaying gastric emptying.

9. A method of reducing gastric motility in a subject in need thereof comprising administering to said subject an amount of an exendin analog effective for reducing gastric motility, wherein said exendin analog is selected from a peptide compound of the formula:

 

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

10Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅, Xaa₆ Xaa₇ Xaa₈ 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

20Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

30Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ 

 

 

 

 

 

 

 

 

 

 

 

35Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein;

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe, Tyr or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu, Ile, Val, pentylglycine or Met;

Xaa₉ is Leu, Ile, pentylglycine, Val or Met;

Xaa₁₀ is Phe, Tyr or naphthylalanine;

Xaa₁₁ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp, Phe, Tyr, or naphthylalanine;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;

Xaa₁₈ is Ser, Thr or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either exendin-3 or exendin-4 and pharmaceutically acceptable salts thereof.

10. A method of reducing gastric motility in a subject in need thereof comprising administering to said subject an amount of an exendin analog effective for reducing gastric motility, wherein said exendin analog is selected from a peptide compound of the formula:

 

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

10Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅, Xaa₆ Xaa₇ Xaa₈ 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

20Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

30Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ 

 

 

 

 

 

 

 

 

 

 

 

35Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein;

Xaa₁ is His or Arg;

Xaa₂ is Ser or Gly;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu or pentylglycine

Xaa₉ is Leu or pentylglycine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile, Val or tert-butylglycine;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp or Phe;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline or N-methylalanine;

Xaa₁₈ is Ser or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either exendin-3 or exendin-4 and pharmaceutically acceptable salts thereof.

13. The method according to claim 9, 10, 11, or 12 wherein said subject is undergoing a gastrointestinal diagnostic procedure.

14. The method according to claim 13 wherein said gastrointestinal diagnostic procedure is a radiological examination.

15. The method according to claim 14 wherein said gastric gastrointestinal diagnostic procedure is magnetic resonance imaging.

16. The method according to claim 9, 10, 11, or 12 wherein said subject is suffering from a gastrointestinal disorder.

11. A method of delaying gastric emptying in a subject in need thereof comprising administering to said subject an amount of an exendin analog effective for delaying gastric emptying, wherein said exendin analog is selected from a peptide compound of the formula:

 

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

10Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅, Xaa₆ Xaa₇ Xaa₈ 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

20Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

30Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ 

 

 

 

 

 

 

 

 

 

 

 

35Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein;

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe, Tyr or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu, Ile, Val, pentylglycine or Met;

Xaa₉ is Leu, Ile, pentylglycine, Val or Met;

Xaa₁₀ is Phe, Tyr or naphthylalanine;

Xaa₁₁ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp, Phe, Tyr, or naphthylalanine;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;

Xaa₁₈ is Ser, Thr or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either exendin-3 or exendin-4 and pharmaceutically acceptable salts thereof.

12. A method of delaying gastric emptying in a subject in need thereof comprising administering to said subject an amount of an exendin analog effective for delaying gastric emptying, wherein said exendin analog is selected from a peptide compound of the formula:

 

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

10Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅, Xaa₆ Xaa₇ Xaa₈ 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

20Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

30Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ 

 

 

 

 

 

 

 

 

 

 

 

35Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein;

Xaa₁ is His or Arg;

Xaa₂ is Ser or Gly;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu or pentylglycine

Xaa₉ is Leu or pentylglycine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile, Val or tert-butylglycine;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp or Phe;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline or N-methylalanine;

Xaa₁₈ is Ser or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either exendin-3 or exendin-4 and pharmaceutically acceptable salts thereof.

17. A method of reducing gastric motility in a subject in need thereof comprising administering to said subject an amount of exendin-4 effective for reducing gastric motility.

19. The method according to claim 17 or 18 wherein said subject is undergoing a gastrointestinal diagnostic procedure.

20. The method according to claim 19 wherein said gastrointestinal diagnostic procedure is a radiological examination.

21. The method according to claim 20 wherein said gastric gastrointestinal diagnostic procedure is magnetic resonance imaging.

22. The method according to claim 17 or 18 wherein said subject is suffering from a gastrointestinal disorder.

18. A method of delaying gastric emptying in a subject in need thereof comprising administering to said subject an amount of exendin-4 effective for delaying gastric emptying.