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Long-acting Y2 and/or Y4 receptor agonists

A technology selected from and analogs, applied in the field of therapeutic peptides, can solve the problem of not expecting circulating peptides to obtain channels, etc.

Inactive Publication Date: 2011-04-20
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the Y5 receptor is expressed in regions of the CNS where circulating peptides are not expected to gain access
[0005] Therefore, PYY and PP are not optimal as drugs for medicinal use due to their relatively broad receptor binding specificity

Method used

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  • Long-acting Y2 and/or Y4 receptor agonists
  • Long-acting Y2 and/or Y4 receptor agonists
  • Long-acting Y2 and/or Y4 receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0343] A. Cell Preparation

[0344] 1. Attached Y-receptor and Gqi5 dual-stabilized CHO cells fed with appropriate antibiotics in DMEM-F12 were seeded into 96-well polylysine (Type D)-coated microplates to near confluence and grown overnight.

[0345] B. Preparation of Reagents

[0346] 2. A 250 mM (100x) stock solution of probenecid (Invitrogen # p36400) was prepared and dissolved in 1 mL of assay buffer.

[0347] 3. Prepare dye loading solution (for one microplate): 10 mL of assay buffer and 100 μL of probenecid (final concentration: 2.5 mM) stock solution, added to the vial of dye loading mix (provided in the kit) . Vortex vigorously.

[0348] c. analysis

[0349] 4. 100 μL of dye loading solution is added to each well of a 96-well plate containing cells / 100 μL of medium (or other buffer, depending on the ligand to be tested). Place the cells in a 37°C / 5% CO2 incubator. Cells were incubated for 1 hour prior to analysis.

[0350] 5. During the incubation of the cells...

Embodiment approach

[0452] 1. A PYY or PP peptide derivative or an analogue thereof, wherein at least one amino acid residue and / or N- and / or C-terminus of the peptide backbone are derived from A-B-C-D-, A-C-D-, A-B-C- or A-C - defined serum albumin binding side chains, wherein

[0453] A-Yes

[0454]

[0455] wherein p is selected from 10, 11, 12, 13, 14, 15 and 16 and d is selected from 0, 1, 2, 3, 4 and 5,

[0456] and -B- is selected from

[0457]

[0458] wherein x is selected from 0, 1, 2, 3 and 4, and y is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

[0459] or A-Yes

[0460]

[0461] wherein n is selected from 12, 13, 14, 15, 16, 17, 18 and 19,

[0462] and -B- is selected from

[0463]

[0464] wherein x is selected from 0, 1, 2, 3 and 4; and

[0465] -C-from

[0466]

[0467] wherein b and e are each independently selected from 0, 1 and 2, and c and f are each independently selected from 0, 1 and 2, provided that when c is 0, b is 1 or 2,

[0468] when...

Embodiment 1

[0734] Manuel synthesized SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:13.

[0735] Synthesis was carried out using the methods "Synthesis of Peptidyl Resin", "Synthesis of Albumin Handle on Peptide", "Final Deprotection and Isolation" described above.

[0736] analyze data

[0737] SEQ ID NO: 1

[0738] Retention time HPLC method I: 25.9min

[0739] Retention time HPLC method II: 5.6min

[0740] Calculated Mw: 4049.6g / mol

[0741] MALDI MS: 4046.4g / mol

[0742] SEQ ID NO: 3

[0743] Retention time HPLC method I: 33.1min

[0744] Retention time HPLC method II: 11.5min

[0745] Calculated Mw: 4973.8g / mol

[0746] MALDI MS: 4972.3g / mol

[0747] SEQ ID NO: 13

[0748] Retention time HPLC method I: 34.0min

[0749] Retention time HPLC method II: 10.2min

[0750] Calculated Mw: 4932.7g / mol

[0751] MALDI MS: 4931.7g / mol

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PUM

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Abstract

The present invention relates to a PYY or PP peptide derivative or analogue thereof derivatised with one or more serum albumin binding side chains comprising a dis-tal tetrazole or carboxylic acid group. Moreover, the invention relates to compositions hereof and methods of treatment of conditions responsive to Y receptor modulation.

Description

technical field [0001] The present invention relates to the field of therapeutic peptides, namely novel extended peptide derivatives such as peptide YY (PYY) and pancreatic polypeptide (PP) derivatives. Background technique [0002] PYY is released by L-cells in the terminal small intestine and colon during meals. PYY activates the Y1, Y2 and Y5 receptor subtypes. Peptide PYY is known to have peripheral effects in the gastrointestinal (GI) tract and also primarily functions as a satiety signal. PYY is released as PYY(1-36) but breaks down to PYY(3-36), which accounts for approximately 50% of circulating PYY. The enzyme responsible for the breakdown is dipeptidyl peptidase IV (DPPIV). PYY(3-36) showed selectivity for Y2 receptors compared to Y1, Y4 and Y5 receptors. [0003] PP is a hormone secreted by endocrine cells in the islets of pancreas and its release is stimulated by food intake. It acts preferably as an agonist for the Y4 receptor, but also exhibits some affini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575A61K38/17
CPCC07K14/575A61K47/48038A61K47/542A61P1/00A61P3/04A61P43/00
Inventor S·奥斯特加尔德S·M·克努德森J·斯佩茨勒R·约根森J·科福德
Owner NOVO NORDISK AS