Template-fixed peptidomimetics with antimicrobial activity
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.
1. A method of treating a disease or infection caused by a Pseudomonas aeruginosa comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I):
wherein
is D Pro- L 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 are, in positions P1 to P12 of the chain:
P1: Thr;
P2: Trp;
P3: Ile;
P4: Dab;
P5: Orn;
P6: D Dab;
P7: Dab;
P8: Trp;
P9 Dab;
P10: Dab;
P11: Ala; and
P12: Ser,
or a pharmaceutically acceptable salt or enantiomer thereof.
2. The method of claim 1 , wherein the subject is suffering from at least one disease selected from the group consisting of respiratory diseases, skin or soil tissue diseases, gastrointestinal diseases, eye diseases, ear diseases, CNS diseases, bone diseases, cardiovascular diseases, gastrourinal diseases, cancer and HIV.
3. The method of claim 1 , wherein the subject is suffering from at least one disease selected from the group consisting of cystic fibrosis, emphysema, asthma, surgical wounds, traumatic wounds, burn wounds, epidemic diarrhea, necrotizing enterocolitis, typhlitis, keratitis, endophthalmitis, otitis, brain abscess, meningitis, osteochondritis, osteomyelitis, endocartitis, pericarditis, epididymitis, prostatitis, urethritis, cancer and HIV.
4. The method of claim 1 , wherein the Pseudomonas aeruginosa is multi-drug resistant.
5. The method of claim 1 , wherein the compound represented by formula (I) is administered in the form of a pharmaceutically acceptable composition, wherein the pharmaceutically acceptable composition comprises one or more physiologically acceptable carriers, diluents, excipients or auxiliaries.
6. The method of claim 1 , wherein at least one additional pharmaceutical agent is administered to the subject.
7. The method of claim 1 , wherein the additional pharmaceutical agent is selected from the group consisting of antimicrobial agents, antibiotic agents, anti cancer agents and antiviral agents.
8. The method of claim 1 , wherein the compound of formula (I) is administered topically.
9. The method of claim 1 , wherein the compound of formula (I) is administered by injection.
10. The method of claim 1 , wherein the compound of formula (I) is administered transdermally, transmucosally, orally or by pulmonary administration.