Synthetic linear apelin mimetics for the treatment of heart failure

A technology of D-L, X1-R-P-R-X5-S-X7-K-G-P-X11-X12-X13, applied in the field of new compositions

Inactive Publication Date: 2015-10-28
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention relates to overcoming the problem of peptide degradation in vivo by modifying the therapeutic peptide or polypeptide of interest i.e. APJ agonists

Method used

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  • Synthetic linear apelin mimetics for the treatment of heart failure
  • Synthetic linear apelin mimetics for the treatment of heart failure
  • Synthetic linear apelin mimetics for the treatment of heart failure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0102] In embodiment 1, the present invention thus provides a peptide or polypeptide of formula (I):

[0103] X1-X2-X3-R-X5-X6-X7-X8-X9-X10-X11-X12-X13

[0104] I

[0105] among them:

[0106] X1 is the N-terminus of the polypeptide and does not exist, is Q, A or pE;

[0107] X2 is R or r;

[0108] X3 is P or 4-PhP;

[0109] X5 is L, Cha, D-L, F, Y, Y(Bzl), 3,4-Cl2-F or NaI;

[0110] X6 is D-amino acid, S or A;

[0111] X7 is D-amino acid, L, H or Aib; and at least one of X6 and X7 is D-amino acid or Aib;

[0112] X8 is K, k, Q or E;

[0113] X9 is G or D;

[0114] X10 is P or pipecolic acid;

[0115] X11 is D-Nle, Nle, f or D-Nva;

[0116] X12 does not exist, is a P or D-amino acid;

[0117] X13 is C-terminal and does not exist, is an F or D-amino acid; and at least one of X11, X12 and X13 is a D-amino acid;

[0118] among them:

[0119] Nle is L-norleucine;

[0120] D-Nle is D-norleucine;

[0121] Nal is L-(naphthyl)alanine;

[0122] D-Nva is D-Norvalin...

Embodiment approach 1a

[0131] In embodiment 1a, the present invention thus provides peptide or polypeptide formula (IA):

[0132] X1-X2-X3-R-X5-X6-X7-X8-G-X10-X11-X12-X13

[0133] IA

[0134] among them:

[0135] X1 is the N-terminus of the polypeptide and does not exist, is Q, A or pE;

[0136] X2 is R or r;

[0137] X3 is P or 4-PhP;

[0138] X5 is L, Cha, D-L, F, Y, Y(Bzl), 3,4-Cl2-F or 2-NaI;

[0139] X6 is D-amino acid or S;

[0140] X7 is D-amino acid, H or Aib; and at least one of X6 and X7 is D-amino acid or Aib;

[0141] X8 is K or k;

[0142] X10 is P or pipecolic acid;

[0143] X11 is D-Nle or Nle;

[0144] X12 does not exist, is a P or D-amino acid;

[0145] X13 is C-terminal and does not exist, is an F or D-amino acid; and at least one of X11, X12 and X13 is a D-amino acid;

[0146] Or an amide, ester or salt of the polypeptide; or a polypeptide substantially equivalent thereto.

[0147] In embodiment 1b, the present invention relates to a peptide or polypeptide of...

Embodiment approach 8

[0156] In embodiment 8, the present invention relates to the polypeptide of any one of embodiments 1 (1A or 1B)-7, having the following formula II:

[0157] X1-R-P-R-X5-a-X7-X8-G-P-X11-X12-X13

[0158] II

[0159] Or the amide, ester or salt of the polypeptide.

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Abstract

The invention relates to novel compositions comprising modified apelin-13 peptide sequences designed to treat cardiovascular disease in subjects to whom they are administered, and which exhibit greater resistance to degradation, and equivalent or greater bioactivity than their wild type counterparts. The invention also relates to methods of making said compositions and using said compositions as pharmaceutically active agents to treat cardiovascular disease.

Description

Field of invention: [0001] The present invention relates to a new composition comprising modified peptide and polypeptide sequences, which are designed to treat cardiovascular diseases in subjects to which they are administered, and the modified peptide and polypeptide sequences show greater Replicas have greater resistance to degradation and equivalent or greater biological activity. The present invention also relates to a method of preparing the composition and a method of using the composition as a pharmaceutically active agent to treat cardiovascular diseases. Background of the invention: [0002] In the western world, the incidence of failure accounts for about 1 / 100 of adults over 65. The most common pathological phenomenon is the chronic defect of myocardial contractility and the resulting cardiac output. Cardiac output is the effective volume of blood ejected from the ventricles over time. Patients with chronic heart failure can have acute decompensated attacks, that is,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00C07K14/00
CPCC07K14/765A61K38/385A61K45/06C07K14/47A61P17/02A61P21/02A61P3/04A61P43/00A61P9/00A61P9/04A61P9/06A61P9/10A61P9/12A61P3/10A61K38/1709A61K2300/00
Inventor F·泽克里八十岛 华杨P·格罗舍J·袁H·赵
Owner NOVARTIS AG
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