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Long-acting Y2 receptor agonists

A technology of derivatives and analogues, applied in the field of therapeutic peptides, can solve problems such as inconvenience to patients

Inactive Publication Date: 2012-07-11
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The relatively short half-life of PYY(3-36) limits the therapeutic use of this peptide, as a steady exposure level would require frequent dosing, which would be very inconvenient for the patient

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0279] analog

[0280] 1. Compared with human PYY(1-36) or human PYY(3-36), there is a PYY analog or derivative thereof with improved stability for C-terminal proteolytic cleavage, which decomposes to reduce said analog or Derivative functionality.

[0281] 2. The PYY analog or derivative thereof according to any one of the preceding embodiments, wherein said PYY analog is not contained in PYY(1-36), PYY(2-36), PYY(3-36), PYY (4-36) or [N-methylTyr36] or [D-Ala3] in any of PYY(5-36).

[0282] 3. The PYY analogue or derivative thereof according to any one of the preceding embodiments, wherein said functionality is determined by assay (IV), in vitro half-life in plasma, as described herein.

[0283] 4. The PYY analogue or derivative thereof according to any one of the preceding embodiments, wherein said analogue or derivative comprises the amino acid sequence of formula (I):

[0284] Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Xaa 11 -Xaa...

Embodiment 1

[0440] Synthesis of resin-bound peptides, SPPS method:The protected peptidyl resin was synthesized according to the Fmoc strategy on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies on a 0.25 mmol scale using DIC and HOAt mediated coupling in NMP. The starting resin for the synthesis of peptide amides is Rink-Amide resin. The protected amino acid derivatives used are standard Fmoc-amino acids (supplied eg by Anaspec, Bachem, Iris Biotech, Watanabe or Novabiochem). In some cases, Fmoc-amino acids are custom synthesized using methods known in the art. The epsilon amino group of the lysine to be acylated was protected with Mtt. In some cases, peptide synthesis can be improved by using dipeptides such as pseudoproline from Novabiochem, Fmoc-Ser(tbu)-ψSer(Me,Me)-OH, see e.g. from Novabiochem 2002 / 2003 or A more recent version of the catalog, or W.R. Sampson (1999), J.Pep.Sci.5, 403.

[0441] Procedure for cleavage of peptides from resin: After synthesis, t...

Embodiment 2

[0492] A comparison of the in vitro half-lives determined for PYY(3-36) analogues in minipig plasma (assay (IV)) and Y2, Y1 and Y5 receptor potency (assays (I), (II) and (III) respectively) shows that in Table 2. This experiment shows that some modifications introduced into PYY prolong the half-life of PYY in vitro.

[0493] Table 2. In Vitro Half-Life of PYY(3-36) Compounds in Minipig Plasma and Potency at Y2, Y1 and Y5 Receptors (Y2R, Y1R and Y5R are Y2, Y1 and Y5 receptors, respectively).

[0494]

[0495]

[0496] n / a: not analyzed

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Abstract

The present invention relates to PYY analogues or derivatives thereof comprising at least one alteration selected from the group consisting of substitutions, insertions, deletions and modifications and optionally a serum albumin binding side chain comprising an alkyl chain with at least 14 carbon atoms. Moreover, the invention relates to compositions hereof and methods of treatment of conditions responsive to Y2 receptor modulation.

Description

field of invention [0001] The present invention relates to the field of therapeutic peptides, namely novel persistent peptide analogs such as peptide YY (PYY) analogs and derivatives thereof, wherein said analogs or derivatives comprise at least one alteration in the peptides selected from : Substitutions, deletions, insertions and modifications that stabilize the peptide analogs against proteolytic degradation. Background of the invention [0002] Peptide tyrosine-tyrosine (PYY) is released by L cells in the distal small intestine and colon during meals. PYY is known to have peripheral effects in the GI tract and also acts centrally as a satiety signal. PYY is released as PYY(1-36), but is cleaved to PYY(3-36), which constitutes approximately 50% of circulating PYY. The enzyme primarily responsible for the degradation to PYY(3-36) in vivo is dipeptidyl peptidase IV (DPP IV). PYY(3-36) is rapidly eliminated by proteases and other clearance mechanisms. The half-life of PY...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/22A61K47/48C07K14/575
CPCC07K14/575A61K38/00A61P3/04A61P3/10
Inventor J·科弗伊德J·奥尔森S·奥斯特伽德R·乔根森
Owner NOVO NORDISK AS
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