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Pituitary adenylate cyclase activating peptide (PACP) receptor (VPAC2) agonists and their pharmacological methods of use

An antibody and drug technology, applied in the field of pituitary adenylate cyclase-activating peptide (PACAP) receptor (VPAC2) agonist and its pharmacological application, can solve problems such as lowering blood sugar

Inactive Publication Date: 2007-02-14
BAYER PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Demonstrated that these insulinotropic polypeptides lower blood glucose in vivo upon glucose stimulation to a greater extent than vehicle controls

Method used

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  • Pituitary adenylate cyclase activating peptide (PACP) receptor (VPAC2) agonists and their pharmacological methods of use
  • Pituitary adenylate cyclase activating peptide (PACP) receptor (VPAC2) agonists and their pharmacological methods of use
  • Pituitary adenylate cyclase activating peptide (PACP) receptor (VPAC2) agonists and their pharmacological methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] Example 1. Peptide Synthesis Method

[0137] [129] Some polypeptides of the present invention were synthesized according to the following general procedure:

[0138]Peptide synthesis was performed under continuous flow conditions using Rapp-Polymere PEG-polystyrene resin (Rapp-Polymere, Tubingen, Germany) by the FMOC / tert-butyl method (Pennington & Dunn, Peptide Synthesis Protocols, Volume 35, 1994). When the synthesis is complete, the peptide is cleaved from the resin and analyzed with TFA / DTT / H 2 O / triisopropylsilane (88 / 5 / 5 / 2) deprotection. Precipitate the peptides from the cleavage mixture with cold diethyl ether. The precipitate was washed three times with cold ether, then dissolved in 5% acetic acid and lyophilized. Peptides were checked by reverse phase chromatography on a YMC-Pack ODS-AQ column (YMC, Inc., Wilmington, NC) on a Waters ALLIANCE(R) system (Waters Corporation, Milord, MA) using water / acetonitrile with 3% TFA As an acetonitrile gradient from 0%-...

Embodiment 2

[0139] Example 2. Peptide Acetylation

[0140] [130] Peptides were synthesized by standard methods well known in the art. Peptides were synthesized with an Applied Biosystems 430A peptide synthesizer using FMOC chemistry with HBTU activation on Rink amide resin and N-terminal acetylation with acetic anhydride. Peptides were cleaved with 84.6% TFA, 4.4% phenol, 4.4% water, 4.4% thioanisole, and 2.2% ethanedithiol. Peptides were precipitated from the cleavage mixture with cold tert-butyl methyl ether. The precipitate was washed with cold ether and dried under argon. The peptide was purified by reverse phase C18 chromatography with a linear water / acetonitrile fraction with 0.1% TFA. Peptide identity was confirmed by MALDI and electrospray mass spectrometry and amino acid analysis.

Embodiment 3

[0141] Example 3. Peptide PEGylation

[0142] [131] By attaching a polyethylene glycol (PEG) moiety to the peptide can reduce renal clearance of the peptide and reduce protease degradation of the peptide, thereby increasing the in vivo half-life of the peptide. The use of VPAC2 receptor agonist peptides is severely limited by their very short in vivo half-life; however, attachment of a PEG moiety (pegylation) extends the half-life of the peptide sufficiently to allow daily to weekly therapy.

[0143] [132] Pegylation can be performed by any method known to those skilled in the art. In this example, however, PEGylation was performed by introducing a unique cysteine ​​mutation into the peptide, followed by the peptide's sulfhydryl group and the methoxy-PEG-maleimide reagent (Nektar (Inhale / Shearwater), San Carlos, CA; NOF, Tokyo, Japan) PEGylate cysteines with stable thioether linkages between the maleimide groups. A unique cysteine ​​can be introduced at the C-terminus of th...

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Abstract

This invention provides novel peptides that function in vivo as agonists of the VPAC2 receptor. These insulin secretagogue polypeptides are shown to lower blood glucose in vivo upon glucose challenge. The polypeptides of this invention are also stable in formulation and have long half-lives. The peptides of the present invention provide a therapy for patients with decreased endogenous insulin secretion, for example, type 2 diabetics. The invention is also directed to a method of treating a metabolic disease in a mammal comprising administering a therapeutically effective amount of the peptides to said mammal.

Description

[0001] The application requires the U.S. provisional application serial number 60 / 539,550 submitted on January 27th, 2004 and the priority of the U.S. provisional application serial number 60 / 566,499 submitted on April 29th, 2004, the content of described document is incorporated in full text here Reference. field of invention [0002] [002] The present invention relates to newly identified polypeptides and their use for therapeutic purposes. More specifically, the polypeptides of the invention can be used to stimulate pancreatic beta cells to release insulin in a glucose-dependent manner, thereby providing a treatment option for individuals suffering from metabolic disorders such as diabetes mellitus or impaired glucose tolerance Minus is a pre-diabetic state. Background of the invention [0003] [003] Diabetes is characterized by impaired glucose metabolism as manifested by elevated blood glucose levels in diabetics, among oth...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K38/16
Inventor K·克莱尔蒙特K·J·伦布T·布克霍尔茨A·I·萨尔哈尼克
Owner BAYER PHARMA CORP
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