Treatment of gestational diabetes

• US 7,452,858 B2
• Filed: 11/17/2005
• Issued: 11/18/2008
• Est. Priority Date: 06/01/1999
• Status: Expired due to Fees

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Prickett, Kathryn S., Hiles, Richard A.
• Primary Examiner(s): Schultz; J D
• Assistant Examiner(s): LIU, SUE XU
• Application Number:
  US11/282,085
• Publication Number:
  US 20060074012A1
• Time in Patent Office: 1,097 Days
• Field of Search: 514/2, 514/3, 514/4, 514/12, 530/300, 530/324, 530/325
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Methods for treating gestational diabetes which comprise administration of an effective amount of an exendin or an exendin agonist, alone or in conjunction with other compounds or compositions that lower blood glucose levels.

Claims

1. A method for treating gestational diabetes mellitus in a human in need thereof comprising subcutaneously injecting the human with about 1 microgram to about 50 micrograms per day of a peptide having the amino acid sequence of SEQ ID NO. 3, SEQ ID NO. 4, or SEQ ID NO. 5 to treat the gestational diabetes mellitus in the human in need thereof;

wherein the peptide does not have the amino acid sequence of SEQ ID NO. 2; and

wherein SEQ ID NO. 3 is;

Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ Ser 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 Try; and

Z is —

OH or —

NH₂;

wherein SEQ ID NO. 4 is;

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 Ala, 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, or

 

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈-Z₂;

Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro. homoproline, 3Hyp, 4Hyp. thioproline, N-alkylglycine, N-alkylpentylglycine, or N-alkylalanine; and

Z₂ is —

OH or —

NH₂;

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

wherein SEQ ID NO. 5 is;

Xaa₁ Xaa₂ Xaa₃ Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆, Xaa₂₇Xaa₂₈-Z₁;

wherein;

Xaa₁ is His. Arg, Tyr, Ala, Norval, Val, or Norleu;

Xaa₂ is Ser, Gly, Ala, or Thr;

Xaa₃ is Ala, Asp, or Glu;

Xaa₄ is Ala, Norval, Val, Norleu, or Gly;

Xaa₅ is Ala or Thr;

Xaa₆ is Phe, Tyr, or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Ala, Norval, Val. Norleu, 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 Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine, or N-alkylalanine; and

Z₂ is —

OH or —

NH₂;

provided that no more than three of Xaa₃, Xaa₄, Xaa₅, Xaa₆, Xaa₈, Xaa₉, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and

provided also that, if Xaa₁ is His, Arg, or Tyr, then at least one of Xaa₃, Xaa₄ and Xaa₉ is Ala.

2. The method of claim 1, wherein the peptide has the amino acid sequence of SEQ ID NO. 3.

3. The method of claim 1, further comprising administering (i) an amylin;

(ii) an amylin agonist peptide;

or (iii) an amylin agonist peptide.

4. The method of claim 2, wherein the peptide having the amino acid sequence of SEQ ID NO. 3 is a peptide having the amino acid sequence of SEQ ID NO. 26.

16. The method of claim 1, wherein the peptide has the amino acid sequence of SEQ ID NO. 4.

17. The method of claim 1, wherein the peptide has the amino acid sequence of SEQ ID NO. 5.

5. A method for treating gestational diabetes mellitus in a subject in need thereof comprising peripherally administering to the subject a therapeutically effective amount of a peptide having the amino acid sequence of SEQ ID NO. 3, SEQ ID NO. 4, or SEQ ID NO. 5 to treat the gestational diabetes mellitus in the subject in need thereof;

wherein the peptide does not have the amino acid sequence of SEQ ID NO. 2; and

wherein SEQ ID NO. 3 is;

Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₄Ser 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 Try; and

Z is —

OH or —

NH₂;

wherein SEQ ID NO. 4 is;

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 Ala, 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, or

 

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈-Z₂;

Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine, or N-alkylalanine; and

Z₂ is —

OH or —

NH₂;

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

wherein SEQ ID NO. 5 is;

Xaa₁ Xaa₂ Xaa₃ Xaa₄ 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, Tyr, Ala, Norval, Val, or Norleu;

Xaa₂ is Ser, Gly, Ala, or Thr;

Xaa₃ is Ala, Asp, or Glu;

Xaa₄ is Ala, Norval, Val, Norleu, or Gly;

Xaa₅ is Ala or Thr;

Xaa₆ is Phe, Tyr, or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Ala, Norval, Val. Norleu, 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 Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine, or N-alkvlalanine; and

Z₂ is —

OH or —

NH₂;

provided that no more than three of Xaa₃, Xaa₄, Xaa₅, Xaa₆, Xaa₈, Xaa₉, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and

provided also that, if Xaa₁ is His, Arg, or Tyr, then at least one of Xaa₃, Xaa₄ and Xaa₉ is Ala.

6. The method of claim 5, wherein the peptide has the amino acid sequence of SEQ ID NO. 3.

7. The method of claim 5, wherein the peptide is continuously administered.

8. The method of claim 5, wherein the administration is by injection.

9. The method of claim 8, wherein the injection is a subcutaneous injection.

10. The method of claim 5, wherein the therapeutically effective amount is 1 microgram to 1 milligram per day.

11. The method of claim 5, wherein the therapeutically effective amount is 1 microgram to 100 micrograms per day.

12. The method of claim 5, wherein the therapeutically effective amount is 1 microgram to 50 micrograms per day.

13. The method of claim 5, further comprising administering (i) an amylin;

(ii) an amylin agonist peptide;

or (iii) an amylin and an amylin agonist peptide.

14. The method of claim 5, wherein the subject is a human.

15. The method of claim 6, wherein the peptide having the amino acid sequence of SEQ ID NO. 3 is a peptide having the amino acid sequence of SEQ ID NO. 26.

18. The method of claim 5, wherein the peptide has the amino acid sequence of SEQ ID NO. 4.

19. The method of claim 5, wherein the peptide has the amino acid sequence of SEQ ID NO. 5.