Template-fixed beta-hairpin peptidomimetics with protease inhibitory activitiy

a technology of protease inhibitor and template, which is applied in the field of template-fixed beta-hairpin peptidomimetics, can solve the problems of low selectivity and particularly high potency of previously disclosed molecules, and achieves low hemolytic activity, high selective serine protease inhibitory activity, and facilitate structure-activity studies

Inactive Publication Date: 2014-07-31
UNIV ZURICH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010]These methods allow the synthesis and screening of large hairpin mimetic libraries, which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with highly potent and selective serine protease inhibitory activity, oral bioavailability, low hemolytic activity to human red blood cells and low cytotoxicity.

Problems solved by technology

Chem Bio Chem 2002, 3, 318-323 but the 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 activitiy
  • Template-fixed beta-hairpin peptidomimetics with protease inhibitory activitiy
  • Template-fixed beta-hairpin peptidomimetics with protease inhibitory activitiy

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examples

1. Peptide Synthesis

Coupling of the First Protected Amino Acid Residue to the Resin

[0441]0.5 g of 2-chlorotritylchloride resin (Barbs et al. Tetrahedron Lett. 1989, 30, 3943-3946) (0.83 mMol / g, 0.415 mmol) was filled into a dried flask. The resin was suspended in CH2Cl2 (2.5 ml) and allowed to swell at room temperature under constant stirring for 30 min. The resin was treated with 0.415 mMol (1 eq) of the first suitably protected amino acid residue (see below) and 284 μl (4 eq) of diisopropylethylamine (DIEA) in CH2Cl2 (2.5 ml), the mixture was shaken at 25° C. for 4 hours. The resin colour changed to purple and the solution remained yellowish. The resin was shaken (CH2Cl2 / MeOH / DIEA: 17 / 2 / 1), 30 ml for 30 min; then washed in the following order with CH2Cl2 (1×), DMF (1×), CH2Cl2 (1×), MeOH (1×), CH2Cl2(1×), MeOH (1×), CH2Cl2 (2×), Et2O (2×) and dried under vacuum for 6 hours. Loading was typically 0.6-0.7 mMol / g.

[0442]The following preloaded resins were prepared: Fmoc-Pro-2-chlorotr...

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Abstract

Template-fixed β-hairpin peptidomimetics of the general formulaewherein Z is a chain of 11 α-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 the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. patent application Ser. No. 11 / 816,589, filed on Aug. 17, 2007, which application is the National Stage of International Application No. PCT / EP2005 / 001622, filed Feb. 17, 2005, the entire contents of each of which is incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention provides template-fixed β-hairpin peptidomimetics incorporating a template-fixed chain of 11 α-amino acid residues which, depending on their position in the chain, are Gly, or Pro, or Pro(4NHCOPhe), or are of certain types, as defined hereinbelow. These template-fixed β-hairpin peptidomimetics are useful as inhibitors of protease enzymes. They are especially valuable as inhibitors of various serine proteases such as human cathepsin G, elastase, or tryptase. In addition the present invention provides an efficient process by which these compounds can, if desired, be made in library-format.[0003...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K7/06C07K1/06
CPCC07K1/061C07K7/06A61K38/00C07K7/08C07K7/64A61P25/00A61P29/00A61P31/00A61P35/00A61P37/00A61P43/00A61P9/00A61K38/04A61K38/08A61K38/10
Inventor DEMARCO, STEVEN J.MOEHLE, KERSTINHENZE, HEIKOSELLIER, ODILEJUNG, FRANCOISEGOMBERT, FRANKOBRECHT, DANIELLUDIN, CHRISTIAN
Owner UNIV ZURICH
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