Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

Patent metadata

Field	Value
Publication number	US-10100084-B2
Application number	US-201615170233-A
Country	US
Kind code	B2
Filing date	Jun 1, 2016
Priority date	Feb 17, 2005
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

Template-fixed β-hairpin peptidomimetics of the general formulae

wherein 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.

First claim

The invention claimed is:

1. A method for treating a disease by inhibiting a protease enzyme in a subject in need thereof, the method comprising administering an effective amount of a compound of formula (I):

in which

is a dipeptide made up of two different amino acid building blocks, the dipeptide being D Pro- L Pro, and
Z is an undecapeptide chain made up of eleven amino acid residues, in which
P1 is selected from Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, or Leu;
P2 is selected from Cys, Glu, Nle, Thr, or Gln;
P3 is selected from Thr, Ala, or Abu;
P4 is selected from Lys, Nle, Ala, Abu, or Thr;
P5 is selected from Ser, AlloThr, or Dpr;
P6 is selected from Ile, C 5 al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu, or Asp;
P7 is Pro;
P8 is selected from Pro, Ala, or Pro(4NHCOPhe);
P9 is selected from Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, or Thr;
P10 is selected from Cys, Arg, Nle, Gln, Lys, Met, Thr, or Ser; and
P11 is selected from Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Phe, Asp, Asn, or Thr,

two residues of Cys, which are present as the P2 and the P10 residues, being linked by a disulfide bridge formed by replacement of the two —SH groups in the two residues of Cys by one —S—S— group, in free form, an enantiomer or in a pharmaceutically acceptable salt form.

2. The method according to claim 1 , wherein said inhibition treats an infection in a healthy individual or slows the progression of an infection in an infected patient.

3. The method according to claim 1 , wherein the protease enzyme is cathepsin G.

4. The method according to claim 1 , wherein the protease enzyme is elastase.

5. The method according to claim 1 , wherein the protease enzyme is tryptase.

6. The method according to claim 1 , wherein a pharmaceutical composition comprises the compound of formula (I) as an active ingredient, and wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

7. The method according to claim 6 , characterized in that the pharmaceutical composition is in the form of a tablet, a dragee, a capsule, a lozenge, a pill, a powder, a liquid, a solution, a syrup, an elixir, a slurry, a suspension, an emulsion, a gel, a cream, an ointment, a plaster, a spray, a nebulizer, an inhaler, an insufflator, a suppository, a sustained-release system, a long acting formulation, a depot preparation or a liposome.

8. The method of claim 1 , wherein the disease is selected from the group consisting of cancer, an inflammatory disease, an infection, a cardiovascular disease, an immunological disease, a neurodegenerative disease, and a pulmonary disease.

9. The method of claim 1 , wherein the compound of formula (I) is in the form of an enantiomer.

Assignees

• Polyphor Ltd
• Univ Zuerich

Inventors

• Demarco Steven J
• Moehle Kerstin
• Henze Heiko
• Sellier Odile
• Jung Francoise
• Gombert Frank
• Obrecht Daniel
• Ludin Christian

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title