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Stabilized exendin-4 compounds

a technology of exendin-4 and compound, applied in the direction of peptide/protein ingredients, peptide sources, metabolism disorders, etc., can solve the problem of glp-1's short half-life, and achieve the effects of stable exendin-4 compound and related composition, improved consistency between lots, and more reliable activity

Inactive Publication Date: 2009-08-20
ZEALAND PHARM AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides stabilized Exendin-4 compounds and related compositions with improved stability and consistency over prior Exendin-4 compositions. The stabilized compounds have modified amino acids residues at positions Gln13, Met14, Trp25, or Asn28 of the Exendin-4 molecule. The modified amino acids can be made through standard techniques or exposure to reactive conditions. The stabilized compounds have better reproducible and consistent agonist activity, providing more reliable and consistent dosing and therapeutic activity. The invention also provides pharmaceutically acceptable salts or solvates of the stabilized compounds.

Problems solved by technology

However, a major pharmacological problem with native GLP-1 is its short half-life.

Method used

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Examples

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example 1

Stabilization of Exendin-4 and Related Molecules by Structural Isomerization and / or Oxidation

[0222]Pharmaceutical compositions of Exendin-4(1-39) or a variant, analogue, or derivative thereof or aqueous solutions of Exendin-4(1-39) or a variant, analogue, or derivative thereof can be stabilized by oxidation or functional isomerization at various points in the Exendin-4(1-39) sequence.

[0223]Storage of the Exendin-4(1-39) or a variant, analogue, or derivative thereof in an aqueous solution at a temperature of between about 0° C. and about 50° C., more particularly between about 4° C. and room temperature can induce a structural rearrangement at the 28-L-Asparaginyl residue of the Exendin-4(1-39) peptide. Suitable aqueous solutions are not particularly limited and may include aqueous pharmaceutical compositions which may have one or more additional additives to facilitate administration to a patient or to stabilize or solublize the Exendin-4(1-39) or a variant, analogue, or derivative ...

example 2

Synthesis of Compound 5, 6 and 14 (Stabilized Derivatives of Compound 1)

[0229]Compound 1 (des Pro36 Exendin-4 (1-39)-K6; SEQ ID NO:1) has the structure shown in FIG. 1 and it was made using the Merrifield technique. See the PCT / DK00 / 00393 application, for example, for more information.

[0230]About 458 mg of Compound 1 was dissolved in 100 mM NH4HCO3 pH 7.9 to a concentration of 10 mg / mL. The solution was incubated at 40° C. for 6 days to yield approx. 20% Compound 5, 10% Compound 14 and 50% Compound 6.

[0231]The stabilized product Compound 5 and Compound 6 can be purified by preparative RP-HPLC isocratic elution or using a gradient, respectively. Identification is accomplished by relative retention time in combination with Amino acid Sequencing and LC-MS (ESI+ / TOF)

example 3

Synthesis of a Compound 7 (Stabilized Derivative of Compound 1)

[0232]About 424 mg of Compound 1 was dissolved in 100 mM NH4HCO3 pH 7.9 to a concentration of 10 mg / mL. The solution was incubated at 40° C. for 5 days to yield approx. 20% Compound 5, 60% Compound 6. Compound 6 was purified by preparative RP-HPLC. Approximately 100 mg Compound 6 was obtained and lyophilised. About 100 mg Compound 6 was reconstituted in 100 mM NaH2PO4 buffer and adjusted to pH 5.3 with NaOH to a concentration of 5 mg / mL. The solution was incubated at 40° C. for 5 days to yield approximately 40% Compound 7.

[0233]The stabilized product Compound 7 can be purified by preparative RP-HPLC gradient elution. Identification is accomplished by relative retention time in combination with LC-MS (ESI+ / TOF).

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Abstract

The present invention discloses compositions comprising a stabilized Exendin-4 (1-39) and related compounds. The invention describes stabilized Exendin-4 agonists that include at least one modified amino acid residue particularly at positions Gln13, Met14, Trp25, or Asn28 of the Exendin-4 (1-39) molecule. Disclosed are preferred modifications of deaminated, hydrolyzed, oxidized, or isomerized reaction products of the specified amino acid residues corresponding to the same positions in the Exendin-4 (1-39) molecule. The invention also relates to methods of making and using the stabilized Exendin compounds, such as for the treatment of diabetes.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 529,858, filed Apr. 26, 2006, which is the national phase of International Application No. PCT / DK2003 / 000651, filed Oct. 2, 2003, which, in turn, claims the benefit of U.S. Provisional Application No. 60 / 415,626, filed Oct. 2, 2002. Each of these applications is hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates to stabilized Exendin-4 compounds and related molecules. In one aspect the invention provides stabilized Exendin-4 agonists that include at least one modified amino acid residue particularly at positions Gln13, Met14, Trp25, or Asn28 of the Exendin-4 (1-39) molecule. Preferred modifications are deaminated, hydrolyzed, oxidized, or isomerized reaction products of the specified amino acid residues corresponding to the same positions in the Exendin-4 (1-39) molecule. Also provided are methods of making and using the stabilized E...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/127C07K14/47A61K38/17A61P3/10A61K38/22C07K14/575
CPCA61K38/00C07K14/57563A61P1/00A61P3/00A61P3/04A61P3/06A61P3/10A61P9/10A61P25/18C07K14/46C07K14/47C07K14/575
Inventor EBBEHOJ, KIRSTENJEPSEN, TRINEKNUDSEN, CARSTEN BOYELARSEN, BJARNE DUEKNOTT, DAVID
Owner ZEALAND PHARM AS
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