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Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

A definition, compound technology, applied in the field of template-immobilized β-hairpin peptidomimetics with protease inhibitory activity, capable of solving the problem of not exhibiting high selectivity and particularly high potency

Active Publication Date: 2015-12-02
POLYPHOR AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Discovery of binding to templates has been described in the literature (D, Obrecht, M. Altorfer, J.A. Robinson, Adv. Med. Chem. 1999, 4, 1-68; J.A. Robinson, Syn. Lett. 2000, 4, 429-441). Clamp mimetics, template-fixed peptide mimetics that inhibit serine proteases and methods of synthesizing them have been described in International Patent Application WO2003 / 054000A1 and DescoursA, MoehleK., RenardA, RobinsonJ. ChemBioChem2002, 3, 318-323, but these previously disclosed Molecules do not exhibit high selectivity and particularly high potency

Method used

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  • Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity
  • Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity
  • Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0595] Example 1 (15.37), Example 2 (11.54), Example 3 (7.82), Example 4 (8.62), Example 5 (16.51), Example 6 (13.67), Example 7 (3.61), implementation Example 8 (4.11), Example 9 (5.82), Example 10 (7.98), Example 11 (8.38), Example 12 (6.80), Example 13 (7.41), Example 14 (6.20), Example 15 (8.68), Example 16 (9.82), Example 17 (5.59), Example 20 (7.32), Example 21 (8.66), Example 22 (8.68), Example 23 (12.66), Example 24 (8.67), Example 25 (7.53), Example 26 (9.02), Example 27 (8.06), Example 28 (9.62), Example 29 (8.78), Example 30 (10.49), Example 31 ( 5.50), Example 32 (7.45), Example 33 (8.39), Example 34 (10.16), Example 35 (9.04), Example 36 (10.98), Example 37 (7.56), Example 38 (9.29 ), Example 39 (8.32), Example 40 (10.11), Example 41 (7.23), Example 42 (8.83), Example 43 (7.92), Example 44 (9.87), Example 45 (8.26) , Example 52 (6.20), Example 53 (8.68), Ex54 (9.82), Example 55 (5.59), Example 56 (6.06), Example 57 (6.47), Example 58 (7.32), Example 59 (8.68), ...

Embodiment 46

[0596] Example 46 is shown in Table 1. Peptides were synthesized starting from the amino acid Pro grafted to the resin. The starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above. According to the procedure described above, a linear peptide was synthesized on a solid support with the following sequence: Resin-Pro- D Asp(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Afterwards, disulfide bond formation was followed as described in Procedure B, and the peptide was cleaved from the resin, cyclized, deprotected, and purified.

[0597] Using the analytical method described above, determine the HPLC-retention time (minutes):

[0598] Example 46 (8.94).

Embodiment 47

[0599] Example 47 is shown in Table 1. Peptide synthesis begins with the amino acid Asp grafted to the resin. The starting resin was Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as described above. According to the procedure described above, a linear peptide was synthesized on a solid support with the following sequence: Resin-Asp(OtBu)- D Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Afterwards, disulfide bond formation was followed as described in Procedure B, and the peptide was cleaved from the resin, cyclized, deprotected, and purified.

[0600] Using the analytical method described above, determine the HPLC-retention time (minutes):

[0601] Example 47(7.29).

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Abstract

The invention provides a template-fixed beta-hairpin peptidomimetics with protease inhibitory activity or salts thereof. The template-fixed beta-hairpin peptidomimetics have a general formula (I) as described in the specification, wherein Z is a chain of 11 alpha-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, or Pro, or Pro (4NHCOPhe), or of certain types which, as remaining symbols in the formula, are defined in the specification and the claims. The template-fixed beta-hairpin peptidomimetics have the property of inhibiting protease (especially serine proteinase, and in particular, cathepsin G, elastase, or tryptase). The beta-hairpin peptidomimetics can be produced through a method based on the strategy of hybrid solid phase-liquid phase synthesis.

Description

[0001] This application is a divisional application of the patent application with the application number 200580049141.1, the application date is February 17, 2005, and the invention title is "template-immobilized β-hairpin peptide mimetic with protease inhibitory activity". technical field [0002] The present invention provides template-immobilized β-hairpin peptidomimetics comprising a template-immobilized chain of 11 α-amino acid residues recapitulating that their positions in the chain are Gly or Pro or Pro(4NHCOPhe), or of certain kinds as defined below. These template-immobilized β-hairpin peptidomimetics are useful as inhibitors of proteases. They are especially useful as inhibitors of different serine proteases such as human cathepsin G, elastase or tryptase. Furthermore, the present invention provides an efficient method by which these compounds can be produced in library form, if desired. [0003] The β-hairpin peptidomimetics of the present invention exhibit enha...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P35/00A61P29/00A61P31/00A61P9/00A61P37/02
CPCY02P20/55
Inventor S·J·德马科K·默勒H·亨策O·塞利耶F·荣格F·贡贝特D·奥伯莱希特C·卢丁
Owner POLYPHOR AG
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