Template-fixed peptidomimetics with antimicrobial activity

Patent metadata

Field	Value
Publication number	US-10730912-B2
Application number	US-201615392586-A
Country	US
Kind code	B2
Filing date	Dec 28, 2016
Priority date	Jan 16, 2006
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Template-fixed β-hairpin peptidomimetics of the general formula

wherein Z is a template-fixed chain of 12 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 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 selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa . They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections.

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 compound represented by the following formula (I):

is D Pro- L Pro or L Pro- D Pro and Z is a chain of 12 α-amino acid residues, wherein the positions of the amino acid residues in the chain are counted starting from the N-terminal amino acid, wherein the amino acid residues in positions P1 to P12 of the chain are
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Gly, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, D Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, D Val, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Aib, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Abu, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Leu, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ile, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Nle, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Nva, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Chg, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Cha, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Gln, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Asp; Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Glu, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Thr, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Pro, Dab;
Cit, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Tyr, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Tyr, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, His, Trp, Dab, Dab, Ala, Dab;
Ala, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Ala, Trp, Ile, Dab, Dab, Dab, Dab, Trp, Dab, Dab, Val, Dab;
Thr, Trp, Ile, Lys, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Lys, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Lys, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Lys, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Lys;
Thr, Trp, Ile, Gln, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Gln, Lys, Dab, Dab, Trp, Dab, Dab, Val, Dab;
Thr, Trp, Nle, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Val, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Chg, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Cha; Dab, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Hse, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, t-BuG, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Cpa, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Dab, Trp, Dab, Dab, Asn, Dab;
Thr, Trp, Ile, Dab, Lys, Dab, Gln, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Gln, Lys, Dab, Dab, Trp, Dab, Dab, Ala, Gln;
Thr, Trp, Ile, Dab, Lys, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Asp, Tyr, Ile, Dab, Lys, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Asp, Tyr, Ile, Dab, Orn, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Glu, Trp, Ile, Dab, Lys, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Glu, Trp, Ile, Dab, Lys, D Dab, Dab, Trp, Dab, Dab, Ala, Gln;
Glu, Trp, Ile, Dab, Lys, D Dab, Dab, Trp, Dab, Dab, Ala, Dap;
Glu, Trp, Ile, Dab, Orn, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Orn, D Dab, Dab, Trp, Dab, Dab, Ala, Dab;
Thr, Trp, Ile, Dab, Orn, D Dab, Dab, Trp, Dab, Dab, Ala, Ser; or
Glu, Trp, Ile, Gln, Lys, Dab, Dab, Ser, Dab, Dab, Ala, Ser,

or a pharmaceutically acceptable salt or enantiomer thereof.

2. An enantiomer of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is therapeutically active.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which has selective antimicrobial activity against Pseudomonas aeruginosa.

5. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically inert carrier.

6. The pharmaceutical composition of claim 5 , which is in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary, or inhalation administration.

7. The pharmaceutical composition of claim 5 , which is in the form of a tablet, dragee, capsule, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, spray, nebuliser, or suppository.

Assignees

• Polyphor Ltd
• Univ Zuerich

Inventors

• Demarco Steven J
• Vrijbloed Wim
• Dias Ricardo
• Robinson John Anthony
• Srinivas Nityakalyani
• Gombert Frank
• Obrecht Daniel

Classifications

• C07K17/00 Primary

  Carrier-bound or immobilised peptides (carrier-bound or immobilised enzymes C12N11/00); Preparation thereof · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• A61K38/04

  Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof ({enzyme inhibitors A61K38/005;} gastrins {A61K38/2207}, somatostatins A61K38/31, melanotropins A61K38/34 {; protease inhibitors A61K38/55}) · CPC title

• C07K14/00

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title

• A61P27/02

  Ophthalmic agents · CPC title