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Exendin-4 derivatives as dual glp1/glucagon agonists

A solvate and peptide compound technology, applied in the direction of glucagon, hormone peptides, specific peptides, etc., can solve the chemical instability of exendin-4 and other problems

Active Publication Date: 2019-07-05
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, due to 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 ( WO2004 / 035623), exendin-4 is chemically unstable

Method used

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  • Exendin-4 derivatives as dual glp1/glucagon agonists
  • Exendin-4 derivatives as dual glp1/glucagon agonists
  • Exendin-4 derivatives as dual glp1/glucagon agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0570] Synthesis of SEQ ID NO:4

[0571] Solid-phase synthesis of Novabiochem Rink-Amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamide at 100-200 mesh, loading 0.34mmol / g base-norleucylaminomethyl resin). The Fmoc-synthesis strategy was performed using HBTU / DIPEA-activation. In the solid phase synthesis protocol, Fmoc-Lys(ivDde)-OH at position 14 and Boc-His(Boc)-OH at position 1 were used. The ivDde group was removed 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). Thereafter Palm-Glu(γОSu)-OtBu was coupled to the liberated amino group. Peptides were cleaved from the resin using King's mixture (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified by preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile / water gradient (both buffers with 0.1% TFA).

[...

Embodiment 2

[0574] Synthesis of SEQ ID NO:5

[0575] Solid-phase synthesis of Novabiochem Rink-Amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamide at 100-200 mesh, loading 0.34mmol / g base-norleucylaminomethyl resin). The Fmoc-synthesis strategy was performed using HBTU / DIPEA-activation. In the solid phase synthesis protocol, Fmoc-Lys(ivDde)-OH at position 14 and Boc-His(Boc)-OH at position 1 were used. The ivDde group was removed 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). Thereafter Palm (γОSu) was coupled to the liberated amino group. Peptides were cleaved from the resin using King's mixture (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified by preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile / water gradient (both buffers with 0.1% TFA).

[0576] Fi...

Embodiment 3

[0578] Synthesis of SEQ ID NO:6

[0579] Solid-phase synthesis of Novabiochem Rink-Amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamide at 100-200 mesh, loading 0.34mmol / g base-norleucylaminomethyl resin). The Fmoc-synthesis strategy was performed using HBTU / DIPEA-activation. In the solid phase synthesis protocol, Fmoc-Lys(ivDde)-OH was used at positions 14 and 40, and Boc-His(Boc)-OH was used at position 1. The ivDde group was removed 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). Thereafter Palm-Glu(γОSu)-OtBu was coupled to the liberated amino group. Peptides were cleaved from the resin using King's mixture (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The crude product was purified by preparative HPLC on a Waters column (Sunfire, Prep C18) using an acetonitrile / water gradient (both buffers wit...

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PUM

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Abstract

The present invention relates to exendin-4 derivatives and their medical use, for example for the treatment of conditions of the metabolic syndrome, including diabetes and obesity, and for reducing excessive food intake.

Description

[0001] field of invention [0002] The present invention relates to exendin-4 peptide analogs which, in contrast to the pure GLP-1 agonist exendin-4, activate both the GLP1 and glucagon receptors, and to Their medical uses, for example, in the treatment of metabolic syndrome conditions, including diabetes and obesity, and for reducing excessive food intake. [0003] Background of the invention [0004] Exendin-4 is a 39 amino acid peptide produced by the salivary glands of Heloderma suspectum (Eng, J. et al., J. Biol. Chem., 267:7402-05, 1992 ). Exendin-4 is an activator of the glucagon-like peptide-1 (GLP-1) receptor, however it does not significantly activate the glucagon receptor. [0005] Exendin-4 has many of the glucoregulatory effects observed with GLP-1. Clinical and nonclinical studies have shown that exendin-4 has several beneficial antidiabetic properties, including glucose-dependent enhancement of insulin synthesis and secretion, glucose-dependent inhibition of g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K14/605A61K38/26
CPCC07K14/575C07K14/605A61K38/00A61K38/2264A61K38/26A61K38/28A61K45/06A61P1/04A61P1/16A61P25/36A61P3/00A61P3/04A61P3/06A61P3/08A61P9/00A61P9/10A61P9/12A61P3/10Y02A50/30A61K2300/00
Inventor T·哈克M·瓦格纳B·亨克尔S·施滕格林A·埃弗斯M·博萨特
Owner SANOFI SA
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