Peptide derivative

A peptide chain and formula technology, applied in the field of new peptides, can solve problems such as unknown ligands

Inactive Publication Date: 2001-12-26
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the natural ligand of APJ and its partial peptide sequence are described in WO99 / 33976 (Japanese Patent Application No. 220853-1998), artificially modified natural ligands such as natural ligands have one or more constitutive amino acids Ligands that are substituted by other amino acids or those that have one or more constitutive amino acid side chains replaced by corresponding substituents are completely unknown

Method used

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  • Peptide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0398] Example 1 (Leu-Val-Gln-Pro-Arg-Gly-Ser-Arg-Asn-Gly-Pro-Gly-Pro-Trp-Gln-Gly-Gly-Arg-Arg-Lys-Phe-Arg-Arg- Production of Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe)

[0399] Introduce Fmoc-Phe-OH into commercially available 2-chlorotrityl resin (Clt resin, 1.3mmol / g) to obtain 0.25mmol Fmoc-Phe-O-Clt resin (0.32mmol / g), take a portion into the peptide In the reaction box of the synthesizer ABI433A, solid-phase synthesis was performed by the Fmoc / DCC / HOBt method. As the protecting group for the side chain of Fmoc amino acid, Pbf group is used to protect Arg, tBu group is used to protect Ser, Boc group is used to protect Trp and Lys, and Trt group is used to protect His, Asn and Gln. The other amino acids used and unprotected side chains were introduced along the N-terminal direction (ie, the direction from Phe to Leu in the above sequence) to obtain the desired protected peptide resin.

[0400] After stirring 50mg (4.45mmol) of the above resin in a 1ml mixture of...

Embodiment 2

[0407] Example 2 (Leu-Val-Gln-Pro-Arg-Gly-Ser-Arg-Asn-Gly-Pro-Gly-Pro-Trp-Gln-Gly-Gly-Arg-Arg-Lys-Phe-Arg-Arg- Production of Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Tyr)

[0408] In Example 1, the amino acid to be introduced into 2-chlorotrityl resin (Clt resin, 1.3mmol / g) was replaced by Fmoc-Tyr(tBu)-OH, and the synthesis and purification were carried out in the same way, and 13.3 was obtained by lyophilization. mg of desired product as a white powder.

[0409] (M+H) + Analysis by mass spectrometry: 4192.0 (calculated value: 4192.3)

[0410] HPLC elution time: 16.9 minutes

[0411] Elution condition:

[0412] Column: YMC A-301-3 (4.6×100mm)

[0413] Eluent: with solution A: 0.1% TFA-water and solution B: acetonitrile containing 0.1% TFA, eluted with a linear concentration gradient of A / B: 100 / 0 to 50 / 50 (25 minutes)

[0414] Flow rate: 1.0ml / min.

Embodiment 3

[0415] Example 3 (production of pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe)

[0416]0.25mmol of Fmoc-Gly-O-Clt resin (0.392mmol / g) obtained by introducing Fmoc-Phe-OH into commercially available 2-chlorotrityl resin (Clt resin, 1.3mmol / g) into a portion of peptide In the reaction box of synthesizer ABI433A, Fmoc-Lys(Boc), Fmoc-His(Trt), Fmoc-Ser(tBu), Fmoc-Leu, Fmoc-Arg(Pbf), Fmoc-Leu, Fmoc-Arg(Pbf), Fmoc-Pro, Fmoc-Arg(Pbf) and Boc-Gln to obtain the desired protected peptide resin.

[0417] After 1 g of resin was placed in 20 ml of a mixture of AcOH:TFA:DCM (1:2:7) and stirred at room temperature for two hours, the mixture was filtered to remove the resin, the solvent was evaporated and lyophilized to obtain 362 mg of the protected peptide (Boc-Gln-Arg(Pbf)-Pro-Arg(Pbf)-Leu-Ser(tBu)-His(Trt)-Lys(Boc)-Gly-OH).

[0418] H-Phe-Obzl-HCl was sequentially condensed with Boc-Pro, Boc-Nle and Boc-Pro to obtain 180 mg of Boc-Pro-Nle-Pro-Phe-Bzl.

[0419] 50 mg Boc-Gln-Arg(...

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Abstract

The present invention relates to novel peptides that are recognized by G protein-coupled receptor proteins. The peptides of the present invention may be used for 1 &cir& development of receptor binding assay system using the expression system of recombinant receptor proteins and screening of candidate compounds for potent pharmaceutical products and 2 &cir& development of pharmaceuticals such as a central nervous function regulator, a circulatory function regulator, a cardiac function regulator, an immune function regulator, a digestive function regulator, a metabolic function regulator or a reproductive organ function regulator.

Description

field of invention [0001] The present invention relates to novel peptides, which are orphan G protein-coupled receptor proteins and have ligand activity against APJ, and their use. Background technique [0002] Many hormones or neurotransmitters regulate the functions of organisms through specific receptors present on cell membranes. These receptors are often referred to as G protein-coupled receptors or 7-segment transmembrane receptors because most of them transduce intracellular signals by activating coupled guanine nucleotide-binding proteins (sometimes abbreviated G proteins) , and have a common structure of 7-segment membrane domains. [0003] Through the interaction of these hormones or neurotransmitters with G protein-coupled receptors, important functions of organisms can be regulated, including maintaining homeostasis, and regulating reproduction, ontogeny, metabolism, growth, nervous system, circulation system, immune system, digestive system, and metabolic syst...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00C07K7/08C07K14/47C07K14/72
CPCA61K38/00C07K7/08C07K14/47C07K14/723C07K14/72
Inventor 北田千惠子日沼州司
Owner TAKEDA PHARMA CO LTD
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