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New compounds as peptidic GLP1/glucagon/GIP receptor agonists

A compound and solvate technology, applied in the field of new compounds as peptide GLP1/glucagon/GIP receptor agonists, can solve the problems of chemical instability of Exendin-4

Pending Publication Date: 2019-07-09
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, exendin-4 is chemically unstable due to oxidation of methionine at position 14 (Hargrove et al., Regul. Pept., 2007, 141, 113-119) and asparagus at position 28. Deamidation and isomerization of amides (WO 2004 / 035623)

Method used

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  • New compounds as peptidic GLP1/glucagon/GIP receptor agonists
  • New compounds as peptidic GLP1/glucagon/GIP receptor agonists
  • New compounds as peptidic GLP1/glucagon/GIP receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0426] Synthesis of SEQ ID NO: 6

[0427] In Novabiochem Rink-amide resin (4-(2',4'-dimethoxypentyl-Fmoc-aminomethyl)-phenoxyacetamido-n-leucylaminomethyl resin), 100-200 mesh The solid-phase synthesis as described in the method was performed on a loading of 0.43mmol / g. The Fmoc synthesis strategy is applied together with HBTU / DIPEA activation. Fmoc-Lys(Mmt)-OH in position 14 and Boc-His(Trt)-OH in position 1 were used in the solid phase synthesis scheme. Cut the Mmt group from the peptide on the resin as described in the method. Thereafter, DIPEA was used as the base to couple Palm-gGlu-gGlu-OSu to the released amino group. The peptide was cleaved from the resin with King's cocktail mix (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (SunfirePrep C18 ODB 5μm 50x150mm) using an acetonitrile / water gradient (both buffers containing 0.1% TFA). The purified peptide was a...

Embodiment 2

[0430] Synthesis of SEQ ID NO: 7

[0431] In Novabiochem Rink-amide resin (4-(2',4'-dimethoxypentyl-Fmoc-aminomethyl)-phenoxyacetamido-n-leucylaminomethyl resin), 100-200 mesh The solid-phase synthesis as described in the method was performed on a loading of 0.43mmol / g. The Fmoc synthesis strategy is applied together with HBTU / DIPEA activation. Fmoc-Lys(Mmt)-OH in position 14 and Boc-His(Trt)-OH in position 1 were used in the solid phase synthesis scheme. Cut the Mmt group from the peptide on the resin as described in the method. Thereafter, DIPEA was used as the base to couple Palm-gGlu-gGlu-OSu to the released amino group. The peptide was cleaved from the resin with King's cocktail mix (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (SunfirePrep C18 ODB 5μm 50x150mm) using an acetonitrile / water gradient (both buffers containing 0.1% TFA). The purified peptide was a...

Embodiment 3

[0434] Synthesis of SEQ ID NO: 11

[0435] In Novabiochem Rink-amide resin (4-(2',4'-dimethoxypentyl-Fmoc-aminomethyl)-phenoxyacetamido-n-leucylaminomethyl resin), 100-200 mesh The solid-phase synthesis as described in the method was performed on a loading of 0.43mmol / g. The Fmoc synthesis strategy is applied together with HBTU / DIPEA activation. Fmoc-Lys(Mmt)-OH in position 14 and Boc-His(Trt)-OH in position 1 were used in the solid phase synthesis scheme. Cut the Mmt group from the peptide on the resin as described in the method. Thereafter, DIPEA was used as the base to couple Palm-gGlu-gGlu-OSu to the released amino group. The peptide was cleaved from the resin with King's cocktail mix (D.S. King, C.G. Fields, G.B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (SunfirePrep C18 ODB 5μm 50x150mm) using an acetonitrile / water gradient (both buffers containing 0.1% TFA). The purified peptide was ...

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PUM

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Abstract

The present invention relates to 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] Invention field [0002] The present invention relates to novel compounds as GLP-1 / glucagon / GIP receptor triple agonists and their uses, for example, in the treatment of metabolic syndrome including diabetes and obesity, and for reducing Excessive food intake. The compounds of the present invention are structurally derived from Exendin-4 and show high solubility and stability under acidic conditions in the presence of antimicrobial preservatives such as m-cresol or phenol, which makes them particularly suitable for use with other Combination of anti-diabetic compounds. [0003] Background of the invention [0004] Bhat et al. (Diabetologia 2013, 56, 1417-1424), Bhat et al. (Biochem Pharmacol. 2013, 85, 1655-62), Gault et al. (J Biol Chem. 2013, 288, 35581-91) and Finan et al. (Nat Med. 2015, 21, 27-36) described the triple agonist of glucagon-like peptide-1 (GLP-1), glucagon, and glucose-dependent insulinotropic polypeptide (GIP) receptors, for example, by in a molecule In ...

Claims

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Application Information

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IPC IPC(8): A61K38/26C07K14/575C07K14/605
CPCA61K38/26C07K14/575C07K14/605A61K38/2278A61P1/00A61P1/16A61P3/04A61P3/06A61P3/10A61P43/00A61P5/50A61P7/12A61P9/10A61P9/12C07K14/57563A61K45/06A61K38/00
Inventor M·博萨A·埃弗斯T·哈克K·洛伦茨D·卡德莱特M·瓦格纳S·法伊弗-马雷克M·洛伦茨
Owner SANOFI SA
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