Peptidic dual GLP-1 / glucagon receptor agonists derived from exendin-4

A receptor and selected technology, applied in the direction of glucagon, peptide/protein components, hormone peptides, etc., can solve the chemical instability of exendin-4 and other problems

Active Publication Date: 2017-02-15
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, because of the oxidation of methionine at position 14 (Hargrove DM et al., Regul. Pept., 141:113-9, 2007) and the deamidation and isomerization of asparagine at position 28 (WO 2004 / 035623), exendin-4 is chemically unstable

Method used

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  • Peptidic dual GLP-1 / glucagon receptor agonists derived from exendin-4
  • Peptidic dual GLP-1 / glucagon receptor agonists derived from exendin-4
  • Peptidic dual GLP-1 / glucagon receptor agonists derived from exendin-4

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0421] Synthesis of SEQ ID NO:8

[0422] The manual synthesis method as described in Methods was performed on dry Rink amide MBHA resin (0.66 mmol / g). The Fmoc-synthesis strategy was implemented with DIC / HOBt-activation. Fmoc-Lys(ivDde)-OH at position 14 and Boc-His(Boc)-OH at position 1 were used. The ivDde-group was cleaved from the peptide on the resin using 4% hydrazine hydrate in DMF according to a modified literature method (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603). Peptides were cleaved from the resin with King's Cocktail (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC using an acetonitrile / water gradient (0.1% TFA in both buffers). Purified peptides were analyzed by LCMS (Method C).

[0423] Deconvolution of the mass signal under the peak with a retention time of 12.66 minutes revealed a peptide mass of 4557.6, which matched the expected value of 4558.22.

Embodiment 2

[0425] Synthesis of SEQ ID NO:11

[0426] The manual synthesis method as described in Methods was performed on dry Rink amide MBHA resin (0.66 mmol / g). The Fmoc-synthesis strategy was implemented with DIC / HOBt-activation. Fmoc-Lys(ivDde)-OH at position 14 and Boc-His(Boc)-OH at position 1 were used. The ivDde-group was cleaved from the peptide on the resin using 4% hydrazine hydrate in DMF according to a modified literature method (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603). Peptides were cleaved from the resin with King's Cocktail (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified via preparative HPLC using an acetonitrile / water gradient (0.1% TFA in both buffers). Purified peptides were analyzed by LCMS (Method D).

[0427] Deconvolution of the mass signal under the peak with a retention time of 14.40 minutes revealed a peptide mass of 4673.6, which matched the expected value of 4673.32.

...

Embodiment 3

[0435] Example 3: Stability and Solubility

[0436] Solubility and stability of the peptide compounds were assessed as described in Methods. The results are given in Table 5.

[0437] Table 5: Stability and Solubility

[0438]

[0439]

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Abstract

Peptidic dual GLP-1 / Glucagon Receptor Agonists derived from Exendin-4 The present invention relates to dual GLP-1 / glucagon receptor agonists or optionally trigonal GLP-1 / glucagon / GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

Description

[0001] field of invention [0002] The present invention relates to exendin-4 (exendin-4) peptide analogs, which activate glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors and optionally glucose- Dependent insulinotropic polypeptide (GIP) receptors, and their medical uses, for example in the treatment of disorders of the metabolic syndrome (including diabetes and obesity) and in reducing excess food intake. [0003] Background of the invention [0004] Exendin-4 is a 39-amino acid peptide produced by the salivary glands of the monster monster (Heloderma suspectum) (Eng J. et al., J. Biol. Chem., 1992, 267, 7402- 05). Exendin-4 is an activator of the glucagon-like peptide-1 (GLP-1) receptor, but it shows only very low activation of the GIP receptor and does not activate the glucagon receptor (see Table 1). [0005] Table 1: Potency (expressed in pM) of increasing concentrations of exendin-4 on GLP-1, GIP and glucagon receptors and cAMP formed measured as described ...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K14/605A61K38/22A61K38/26A61K45/06A61P3/10A61P5/50A61P9/12A61P3/06A61P9/10A61P9/00
CPCA61K45/06C07K14/57563C07K14/605A61K38/00A61K38/26A61P3/04A61P3/06A61P5/50A61P9/00A61P9/10A61P9/12A61P3/10A61K38/2271A61K38/28A61K2300/00
Inventor M·博萨尔特R·埃尔弗特A·艾弗斯T·哈克S·斯坦格林M·瓦格纳K·洛伦茨
Owner SANOFI SA
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