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Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions

A halogen and amino acid technology, applied in the direction of glucagon, hormone peptide, animal/human protein, etc., can solve the problem of short serum half-life

Inactive Publication Date: 2007-08-01
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Currently, there has been a significant problem with therapies involving the use of GLP-1-type molecules due to the rather short serum half-life of this peptide

Method used

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  • Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
  • Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
  • Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0366] Simultaneous solid phase peptide synthesis of 11-segment peptide

[0367] Prepare in position X in batches using the following manual procedures aa10 And X aa11 The dipeptidyl resin containing amino acids is then used on the MPS-396 peptide synthesizer to perform continuous peptide chain extension using automated simultaneous synthesis procedures. The synthesis of N-α-Fmoc-protected biphenylalanine or phenyl-heteroaryl-alanine derivatives used in the manual coupling is described in the above general experimental method, and as Described in Examples 10-16 and 21-22.

[0368] 9-Fmoc-aminoxanthene-3-yloxy-Merrifield resin (Sieber amide resin) in an amount sufficient to synthesize several 11-link analogs was washed with DMF (4×10 mL / g, 5 minutes); Load: 0.5 to 0.7mmol / g) swelling. Then, it was treated twice with 20% piperidine in DMF solution (10 mL / g) for 5 and 15 minutes, respectively, to remove the Fmoc group. The resin was washed with DMF (4×10 mL / g) and NMP (4×10 mL / g). P...

Embodiment 2

[0393] A. General method for the synthesis of N-acylated 11-segment peptide analogs (Scheme 2).

[0394] As shown in Flow Diagram 2, the synthesis of the N-acylated 11-segment peptide analogue is from the protected 11-segment peptidyl-resin intermediate prepared by the method described herein (1) (0.015 mmol) start. Use the method described here to remove the Fmoc group, and use the coupling process described in the general method described here to couple the resulting resin intermediate 2 with the relevant Fmoc protected amino acid or carboxylic acid . In the case where a suitable anhydride is available, the N-acylation is performed using 5 equivalents of anhydride in NMP solution. The resulting N-acylated 11-link analog (3) was cleaved / deprotected according to the general method described herein and purified by preparative HPLC.

[0395] Scheme 2: Synthesis of 11-linked peptide analogs substituted / derivatized with residue #1

[0396]

[0397] B. General formula for the synt...

Embodiment 3

[0406] Use Applied Biosystems Model 433A Peptide Synthesizer for 11-segment peptides Solid phase synthesis of analogs

[0407] The following is a general description of the solid-phase synthesis of typical 11-segment peptide analogs using the upgraded Applied Biosystems Model 433A peptide synthesizer. The upgraded hardware and software of the synthesizer can conduct conductive monitoring of the Fmoc deprotection step along with the coupled feedback control. The procedure allows for synthesis scales in the range of 0.05 to 1.0 mmol.

[0408] The incorporation of the two unnatural C-terminal amino acids related to the simultaneous synthesis of 11-link analogs is as described above. This Fmoc-protected dipeptidyl resin was used in the synthesis of this ABI. The Fmoc-protected dipeptidyl-resin (0.1 mmol) was placed in an appropriately sized container on the instrument, washed 6 times with NMP and treated twice with 22% piperidine / NMP ( Each 2 and 8min.) to deprotect. One or two addi...

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Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1)-receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The peptides of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.

Description

[0001] This application claims the priority of the U.S. Provisional Patent Application Serial No. 60 / 585,358 filed on July 2, 2004 and the U.S. Provisional Patent Application Serial No. 60 / 684,805 filed on May 26, 2005, each of which is hereby All of them are incorporated by reference in their entirety. Invention field [0002] The present invention provides a new human glucagon-like peptide-1 (GLP-1) peptide receptor modulator, agonist or partial agonist, which shows the superior biological properties of the natural peptide GLP-1, and when GLP- 1 When compared with the native sequence, it shows improved stability against proteolytic cleavage and therefore is useful for improving the diabetic condition. Background of the invention [0003] GLP-1 is an important gastrointestinal hormone, which has regulatory functions on glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 30-amino acid peptide derived from preproglucagon, which is synthesized, for exa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605
Inventor W·R·埃温C·马佩利R·B·苏尔斯基T·S·哈克V·G·李D·J·李克辛格R·L·马丁内斯Y·朱
Owner BRISTOL MYERS SQUIBB CO
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