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Modified exendin and exendin agonists

An agonist, polymer technology, applied in the field of modified exendin and exendin agonists, which can solve the problems of increased bioavailability, increased stability, decreased antigenicity and immunogenicity

Inactive Publication Date: 2002-10-02
AMYLIN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PEG modification can lead to increased circulation time, reduced antigenicity and immunogenicity of the peptide, increased solubility, resistance to proteolytic hydrolysis, increased bioavailability, reduced toxicity, increased stability and easier formulation (see, Francis et al., International Journal of Hematology, pp. 68:1-18, 1998), and the problem of using PEGylation (PEGylation) in most cases is that the biological activity is significantly reduced (supra)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-e

[0335] Preparation of Example 1-exendin-3 His Ser Asp Gly Thr Phe Thr Ser Ser Asp Leu Ser Lys Gln Met Glu Glu GluAla Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Ser Gly AlaPro Pro Pro Ser-NH 2 [SEQ.ID NO.1]

[0336] Using Fmoc-protected amino acids (Applied Biosystems, Inc.), in 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethylphenoxyacetamide norleucine MBHA resin (Novabiochem, 0.55mmol / g) Assemble the above amidated peptide. In general, single coupling cycles were used throughout the synthesis and Fast Moc (HBTU activation) chemistry was used. Deprotection of the growing peptide chain (removal of the Fmoc group) was achieved using piperidine. Using a mixture of triethylsilane (0.2 mL), ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) and trifluoroacetic acid (15 mL), the standard method (Introduction to Cleavage Techniques, Applied Biosystems, Inc.), to achieve final deprotection of the entire peptide resin. The peptides were precipitated ...

Embodiment 2

[0339] Example 2- Preparation of exendin-4 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu GluAla Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Ser Gly AlaPro Pro Pro Ser-NH 2 [SEQ.ID NO.2]

[0340] In a similar manner to exendin-3 described in Example 1, using Fmoc-protected amino acids (Applied Biosystems, Inc.), in 4-(2'-4'-dimethoxyphenyl)-Fmocaminomethyl The above amidated peptides were assembled on phenoxyacetamide norleucine MBHA resin (Novabiochem, 0.55 mmole / g), cleaved from the resin, deprotected and purified. Solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used in the analysis. Analytical RP-HPLC of the lyophilized peptide (gradient: 36%-46% solvent B in solvent A in 30 minutes) gave the product peptide with an observed retention time of 14.9 minutes. Electrospray Mass Spectrometry (M): Calculated 4186.6; Found 4186.0-4186.8 (4 batches).

Embodiment 3

[0341] Example 3: Renal clearance

[0342] The kidneys can play a major role in the elimination of certain molecules (drugs, peptides, proteins). For certain molecules, this process begins when the kidneys filter blood at the glomeruli, producing the ultrafiltrate described below. Glomerular filters discriminate not only based on molecular weight but also by acting as a negatively charged selective barrier, facilitating the retention of anionic compounds. The free fraction (not bound to protein) of molecules with a molecular weight of less than 5 kD and an effective half diameter of less than 15 mm in plasma is easily filtered. For larger molecular weight molecules, they are filtered on a more restrictive and limited basis, mainly based on molecular size, structure and net charge. The cut-off point for glomerular filtration lies between retained albumin (67kD) and filtered hemoglobin (68kD). Albumin with an effective half diameter of approximately 36 mm is le...

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Abstract

Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more polyethylene glycol polymers, for example, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and / or slowing gastric emptying or inhibiting food intake.

Description

[0001] related application [0002] This application claims priority to, and the benefit of, US Provisional Patent Application Serial No. 60 / 132,018 filed April 30, 1999, which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more polyethylene glycol polymers (or other molecular weight increasing agents) Peptides, and related articles of manufacture and methods, said novel modified exendins and exendin agonists and related articles of manufacture and methods are useful, for example, in the treatment of diabetes (including type I diabetes and type II diabetes), useful in the treatment of diabetes mellitus by regulating plasma glucose levels and may be used to treat conditions that benefit from the administration of drugs that may be used to modulate glucagon levels or triglyc...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K45/00A61K47/48A61P1/00A61P3/04A61P3/06A61P3/08A61P3/10A61P5/48A61P5/50C07K1/04C07K14/46C07K14/575
CPCA61K38/00A61K47/60A61P1/00A61P3/04A61P3/06A61P3/08A61P3/10A61P5/48A61P5/50C07K14/57563
Inventor A·杨K·普里克特
Owner AMYLIN PHARMA INC
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