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Antagonists of the bradykinin b1 receptor

A peptide antagonist, bradykinin technology, applied in the direction of pancreatic kinin/bradykinin, anti-inflammatory agents, specific peptides, etc., can solve problems such as intolerance to substitution

Inactive Publication Date: 2007-01-17
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because therapeutic peptides often contain only the minimal sequence required for activity, they tend to be small and therefore relatively intolerant of substitutions

Method used

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  • Antagonists of the bradykinin b1 receptor
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  • Antagonists of the bradykinin b1 receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0288] Example 1: Synthesis and purification of B1 receptor peptide antagonists and PEG-coupled B1 receptor peptide antagonists

[0289] The various peptides of the invention are synthesized using synthetic techniques well known in the art. A preferred method of synthesizing the various peptides of the invention utilizes the activation of carbodiimides using the FMOC method, as described below.

[0290] Part 1: Addition of dissolved Fmoc-amino acids to resins using carbodiimide chemistry.

[0291] Fmoc-amino acids (3-4 equivalents) were dissolved into dry DCM / NMP mixture (NMP or DMF was used to aid complete dissolution). N-Hydroxybenzotriazole (HOBt, same as amino acid equivalent) dissolved in NMP was added to the amino acid solution. N,N'-dicyclohexyl-carbodiimide (DCC, same as amino acid equivalent) dissolved in DCM was added to the amino acid solution. The solution was mixed for about 20 minutes. The activated acid solution is then added to the resin (if necessary, the ...

Embodiment 2

[0347] Example 2: Synthesis and purification of PEG-conjugated B1 receptor peptide antagonists using PEG thioesters.

[0348] in 50mM NaHPO 4 , 5 mM EDTA, pH 7, mix a cysteine-containing peptide with PEG-maleimide (2.5-5 mg / ml peptide and react stoichiometrically with a 1.2-fold molar excess of maleimide:thiol) reaction to prepare PEG-conjugated peptides. The reaction was stirred at room temperature (20-25°C) for 18-26 hours. As soon as the stirring is finished, the reaction is terminated with a 10-fold molar excess of β-mercaptoethanol (β-ME):maleimide, and stirred at room temperature for another 30-60 minutes. The reaction mixture was purified by method A as described in the above examples.

Embodiment 3

[0349] Example 3: Synthesis and purification of PEG-conjugated B1 receptor peptide antagonists using PEG thioester or iodoacetate.

[0350] in 50mM NaHPO 4 , 5 mM EDTA, pH 7, react a peptide containing an N-terminal cysteine ​​with PEG-OPTE (o-pyridylthioester) (2.5-5 mg / ml peptide and a stoichiometric excess of 1.2-fold molar activated PEG: peptide) reaction to prepare PEG-conjugated peptides. The reaction was stirred at room temperature (20-25°C) for 18-26 hours. Once the stirring is over, the reaction is terminated with a 10-fold molar excess of cysteine: excess PEG reagent, and stirred at room temperature for another 30-60 minutes. The reaction was purified using Method A described in Example 1 above.

[0351] Alternatively, conjugates can be formed using PEG-iodoacetamide as described above, where the PEG moieties are linked by thioether linkages (Scheme 3). In this case, 1.5 molar equivalents of the activated PEG reactant were used, the reaction time was increased to...

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Abstract

The present invention relates to biologically active peptides and conjugated peptides useful as therapeutic or prophylactic agents against diseases or conditions associated with pathogenic factor B1. In a preferred embodiment of the present invention, biologically active PEG-conjugated peptides are provided. In one aspect of the invention, the pharmaceutically active PEG-conjugated peptides of the invention are useful in the treatment of inflammation or pain.

Description

[0001] This application claims priority to US Provisional Application No. 60 / 513,913, filed October 22, 2003, and US Provisional Application No. 60 / 538,929, filed January 24, 2004, both of which are incorporated herein by reference. Background of the invention [0002] On any given day, more than 2 million people in the United States alone are incapacitated by chronic pain (T.M. Jessell & D.D. Kelly, Pain and Analgesia, PRINCIPLES OFNEURAL SCIENCE, 3rd Edition (E.R. Kandel, J.H. Schwartz , T.M.Jessell, ed., (1991)). Unfortunately, current treatments for pain are only partially effective, and many treatments also have lifestyle-altering, debilitating, and / or dangerous side effects. For example, NSAIDs ("NSAIDs") such as aspirin, ibuprofen, and indomethacin are only moderately effective on inflammatory pain, but they are renally toxic, and high doses tend to cause gastrointestinal irritation, ulcers, bleeding, increased cardiovascular risk, and conscio...

Claims

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Application Information

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IPC IPC(8): A61K47/48C07K7/18A61P29/00A61K47/60
Inventor G·吴Y·-S·李C·V·格格B·C·小艾斯丘T·施托尔茨卢跃列D·C·答米克
Owner AMGEN INC
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