Beta-hairpin peptidomimetics
Inventors
Obrecht, Daniel • Luther, Anatol • Bernardini, Francesca • Zbinden, Peter • BARTHELEMY, Sophie • Lederer, Alexander
Assignees
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Publication Number
US-11753446-B2
Publication Date
2023-09-12
Expiration Date
Abstract
Beta-hairpin peptidomimetics of the general formula (I), cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2], and pharmaceutically acceptable salts thereof, with P1 to P12, T1 and T2 being elements as defined in the description and the claims, have Gram-negative antimicrobial activity to e.g. inhibit the growth or to kill microorganisms such as Klebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichia coli. They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials.These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.
Core Innovation
The invention relates to β-hairpin peptidomimetics of general formula (I), namely cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2](I) compounds and pharmaceutically acceptable salts thereof. The compounds are described as cyclo-based cationic mimetics with a template-stabilized β-hairpin backbone, and the elements T or P are connected in either direction from the carbonyl (C=O) point of attachment to the nitrogen (N) of the next element.
The disclosed structures include interstrand linkage options such as disulfide linkage, lactam linkage, and 1,2,3-triazole linkage between specified residues, including between P2 and P11 and/or between P4 and P9. Optional additional interstrand linkages increase rigidity, and the description provides extensive definitions and constraints for substituents and residue variants used in the general formula (I).
The compounds are described as exhibiting Gram-negative antimicrobial activity, including inhibiting growth and killing of Gram-negative pathogens. Examples explicitly mentioned include Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli.
Claims Coverage
The provided content includes two independent claims. Across these independent claims, the inventive features are directed to administering pharmaceutically acceptable compounds of general formula (I), specifically β-hairpin peptidomimetics with defined cyclo connectivity and defined interstrand linkages, to treat Gram-negative bacterial infections in specified subject contexts.
Cyclo connectivity of general formula (I) from carbonyl attachment to next nitrogen
The compound is cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2](I), wherein the single elements T or P are connected in either direction from the carbonyl (C=O) point of attachment to the nitrogen (N) of the next element.
Disulfide, lactam, or 1,2,3-triazole interstrand linkage in β-hairpin peptidomimetics
The compound is selected from β-hairpin peptidomimetics of general formula (I) having a disulfide linkage; a lactam linkage; or a 1,2,3-triazole linkage between P2 and P11, and/or β-hairpin peptidomimetics having a disulfide linkage; a lactam linkage between P4 and P9; or disulfide linkages between P2 and P11, and P4 and P9.
Treating gram-negative infections with cyclo β-hairpin peptidomimetics for defined infection sites
A method of treating infections by Gram-negative bacteria by administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or pharmaceutical composition, where the Gram-negative infections are respiratory infections, skin or soft tissue infections, gastrointestinal infections, eye infections, ear infections, CNS infections, bone infections, cardiovascular infections, or genitourinary infections; and where the compound is a compound of the general formula (I) or a pharmaceutically acceptable salt thereof.
Treating nosocomial/catheter-related gram-negative infections with cyclo β-hairpin peptidomimetics
A method of treating an infection by Gram-negative bacteria by administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or pharmaceutical composition, where the infection is a nosocomial infection, a catheter-related infection, a non-catheter-related infection, a urinary tract infection, or a bloodstream infection; and where the compound is a compound of the general formula (I) or a pharmaceutically acceptable salt thereof.
Both independent claims require administration of pharmaceutically acceptable compounds of general formula (I), specifically cyclo β-hairpin peptidomimetics with defined carbonyl-to-nitrogen connectivity and defined interstrand linkage types (disulfide, lactam, and/or 1,2,3-triazole between specified positions), with the clinical infection contexts specified as respiratory/skin/gastrointestinal/ocular/ear/CNS/bone/cardiovascular/genitourinary sites in one claim and nosocomial/catheter/urinary tract/bloodstream categories in the other.
Stated Advantages
Improved efficacy.
Reduced hemolysis.
Reduced or no cytotoxicity.
Documented Applications
Used as medicaments to treat infections.
Used as medicaments to prevent infections.
Used as disinfectants.
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