Gip and glp-1 co-agonist compounds

A compound, conjugation technology, applied in the field of medicine, which can solve problems such as low immunogenicity potential

Active Publication Date: 2017-09-26
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, there remains a need to provide a compound with balanced co-agonist activity at the GIP and GLP-1 receptors that provides sufficient stability against DPP IV and other degraded forms, yet retains a low immunogenic potential

Method used

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  • Gip and glp-1 co-agonist compounds
  • Gip and glp-1 co-agonist compounds
  • Gip and glp-1 co-agonist compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] YX 1 EGTFTSDYSIX 2 LDKIAQKAFVQWLIAGGPSSGAPPPS

[0066] where X 1 is Aib;X 2 is Aib; K at position 20 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 18 -CO 2 Chemically modified by H conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO:3)

[0067] Trifluoroacetate

[0068]

[0069] The structure above contains the standard one-letter amino acid code except for residues Aib2, Aib13 and K20, where the structure of the amino acid residues Aib2, Aib13 and K20 has been expanded.

[0070] The peptide of SEQ ID NO: 3 according to the present invention was generated by solid-phase peptide synthesis using the Fmoc / t-Bu strategy on a Symphony automated peptide synthesizer (PTIProtein Technologies Inc.), starting from RAPP AM-Rink amide resin, where 6 equivalents of amino acids activated with diisopropylcarbodiimide (DIC) and hydroxybenzotriazole (HOBt) (1:1...

Embodiment 2

[0076] TX 1 EGTFTSDYSIX 2 LDKIAQKAX 3 VQWLIAGGPSSGAPPPS

[0077] where X 1 is Aib;X 2 is Aib; K at position 20 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 2 -CO-(CH 2 ) 18 -CO 2 H is chemically modified by conjugation to the ε-amino group of the K side chain; X 3 is 1-Nal; and the C-terminal amino acid is amidated to the C-terminal primary amide (SEQ ID NO:4)

[0078] Trifluoroacetate

[0079]

[0080] The above structure contains the standard one-letter amino acid code except for residues Aib2, Aib13, K20 and 1-Nal22, for which the structure of these amino acid residues Aib2, Aib13, K20 and 1-Nal22 has been expanded.

[0081] The peptide of SEQ ID NO: 4 according to the present invention was synthesized similarly to that described in Example 1 above. The following conditions were used for the coupling of Fmoc-1Nal-OH at position 22: 25°C, Fmoc-1Nal-OH (6 equiv), PyBOP (6 equiv) and DIEA (12 equiv) in DMF for 4 hours.

Embodiment 3

[0083] YX 1 EGTFTSDYSIX 2 LDKIAQKAFVQWLIAGGPSSGAPPPS

[0084] where X 1 is Aib;X 2 is Aib; K at position 20 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 16 -CO 2 Chemically modified by H conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO:5)

[0085] Trifluoroacetate

[0086] Similar to what was described in Example 1 above, the compound of SEQ ID NO: 5 according to the present invention was synthesized.

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Abstract

The present invention relates to dual incretin peptide mimetic compounds that agonize receptors for both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and may be useful for treating type 2 diabetes mellitus (T2D).

Description

field of invention [0001] The present invention relates to the field of medicine. More specifically, the present invention relates to dual incretin mimetic compounds that agonize human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and are useful in the treatment of type 2 Diabetes mellitus (T2D). Background technique [0002] T2D is the most common form of diabetes, accounting for approximately 90% of all diabetes. T2D is characterized by high blood sugar levels caused by insulin resistance. The current standard of care for T2D includes diet and exercise and available oral and injectable hypoglycemic drugs. However, many patients with T2D remain inadequately controlled. Currently marketed incretin mimetics or dipeptidyl peptidase IV (DPP-IV) inhibitors utilize only a single established mechanism for glycemic control. There is a need for a compound against T2D that utilizes a dual mechanism of action. [0003] GIP is a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K14/605A61K38/22A61K38/26A61P3/10
CPCC07K14/575C07K14/605A61K38/00A61P3/10A61K38/26A61K38/16A61K45/06A61P43/00C07K14/001A61P3/04C07K14/645A61P3/06
Inventor J·阿尔西纳-费尔南德斯B·K·博奎斯特T·科斯昆R·C·卡明斯
Owner ELI LILLY & CO
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