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Co-agonists of the glucagon and glp-1 receptors

Inactive Publication Date: 2016-04-28
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides peptides that can act as agonists of both the glucagon receptor and GLP-1 receptor, with a relatively balanced activity at both receptors. These peptides have a ratio of EC50 at the glucagon receptor to EC50 at the GLP-1 receptor of about 0.88 to about 1.25, about 0.90 to about 1.25, about 0.90 to about 1.10, about 0.90 to about 1.00, or about 1.0±0.12. These peptides can be used to treat metabolic disorders such as diabetes and obesity.

Problems solved by technology

Nonetheless, the inherent risk of hyperglycemia, especially in insulin resistant states such T2DM, has complicated the translation of these observations to human study.

Method used

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  • Co-agonists of the glucagon and glp-1 receptors
  • Co-agonists of the glucagon and glp-1 receptors
  • Co-agonists of the glucagon and glp-1 receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0261]Procedure for the synthesis of Co-agonist Peptide 1: His1-D-Ser2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys10(γGlu-C16)-Ser-Lys-Tyr-Leu-Asp-Ala-Arg-Ala-Ala-Gln-Asp-Phe22-Val23-Gln-Trp-Leu-Leu-Asp-Thr-CONH2 (SEQ ID NO:6) was as follows.

[0262]The peptide was synthesized on a Rink-amide PEG-PS resin, Champion (Biosearch Technologies (150 μmol, loading 0.28 mmol / g) on a Symphony Protein Technologies Inc apparatus.

[0263]All the amino acids were dissolved at a 0.3 M concentration in a solution of 0.3M HOBt (Hydroxybenzotriazole) in DMF. The acylation reactions were performed for 1 hour with 5-fold excess of activated amino acid over the resin free amino groups. The amino acids were activated with equimolar amounts of HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and a 2-fold molar excess of DIEA (diisopropylethylammine) solution 2M in NMP.

[0264]Double acylation reactions of 45 minutes were performed from His1 to Trp25. The crude peptide (130 mg in 3 ml of D...

example 2

[0266]Procedure for the synthesis of Co-agonist Peptide 2: His1-D-Ser2-Gln-Gly-Thr-Phe-Thr-S er-Asp-Lys10(γGlu-C16)-Ser-Lys-Tyr-Leu-Asp-Val-Arg-Ala-Ala-Gln-Asp-Phe22-Val23-Gln-Trp-Leu-Leu-Asp-Thr-CONH2 (SEQ ID NO:7) was as follows.

[0267]The peptide was synthesized as previously reported for SEQ ID NO: 6 / Example 1

The crude peptide (130 mg in 3 ml of DMSO) was purified by reverse-phase HPLC using preparative Waters Delta-Pak™ C-4 cartridges (40×200 mm, 15 μm, 300 Å) and using as eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile. The following gradient of eluent B was used: 30% B to 30% B over 5 min, 50% B to 50% B over 20 min-80% B, flow rate 80 mL / min, wavelength 214 nm. Yield 16%, 95% pure.

[0268]The final peptide was characterized on an Acquity UPLC Waters Chromatograph, with BEH300 C4 Acquity Waters 2.1×100 mm, 1.7 μm, at 45° C., using H2O, 0.1% TFA (A) and CH3CN, 0.1% TFA (B) as solvents and also characterized by electrospray mass spectrometry on a Acquity SQ Detector...

example 3

[0269]Procedure for the synthesis of Co-agonist Peptide 3: His1-D-Ser2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys10(γGlu-γGlu-C16)-Ser-Lys-Tyr-Leu-Asp-Val-Arg-Ala-Ala-Gln-Asp-Phe22-Val23-Gln-Trp-Leu-Leu-Asp-Thr-CONH2 (SEQ ID NO:8) was as follows.

[0270]The peptide was synthesized as previously reported for Co-agonist Peptide 1. The crude peptide (130 mg in 3 ml of DMSO) was purified by reverse-phase HPLC using preparative Waters Delta-Pak™ C-4 cartridges (40×200 mm, 15 μm, 300 Å) and using as eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile. The following gradient of eluent B was used: 30% B to 30% B over 5 min, 30% B to 60% B over 20 min-80% B, flow rate 80 mL / min, wavelength 214 nm. Yield 20%, >90% pure.

[0271]The final peptide was characterized on an Acquity UPLC Waters Chromatograph, with BEH300 C4 Acquity Waters 2.1×100 mm, 1.7 μm, at 45° C., using H2O, 0.1% TFA (A) and CH3CN, 0.1% TFA (B) as solvents and the following gradient: 35% to 65% B in 4 min, flow 0.4 mL / min. The pept...

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Abstract

Described are peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have relatively balanced agonist activity at the glucagon-like peptide 1 (GLP-1) receptor and the glucagon (GCG) receptor, and the use of such GLP-1 receptor / GCG receptor co-agonists for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit to Provisional Patent Application No. 62 / 068,157 filed Oct. 24, 2014 and Provisional Patent Application No. 62 / 208,869 filed Aug. 24, 2015, which are herein incorporated by reference in their entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY[0002]The sequence listing of the present application is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name “23848_US_NP_SEQLIST_13OCT2015.txt”, creation date of Oct. 13, 2015, and a size of 13.5 Kb. This sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0003](1) Field of the Invention[0004]The present invention relates to peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while...

Claims

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Application Information

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IPC IPC(8): A61K38/26A61K38/28C07K14/605
CPCA61K38/26A61K38/28C07K14/605A61K2300/00A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10
Inventor BIANCHI, ELISABETTACARRINGTON, PAUL E.DENG, QIAOLINNARGUND, RAVIORVIETO, FEDERICAPALANI, ANANDANPESSI, ANTONELLOTUCKER, THOMAS JOSEPHWU, CHENGWEI
Owner MERCK SHARP & DOHME CORP
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