Hybrid amide derivatives of amphotericin B
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Publication Number
US-12655173-B2
Publication Date
2026-06-16
Expiration Date
Abstract
Disclosed are C16 amide derivatives of C2′-epi-amphotericin B (C2′epiAmB) and salts thereof, characterized by improved clinical efficacy with reduced toxicity compared to AmB. Also disclosed are pharmaceutical compositions, comprising any of the disclosed compounds or salts thereof, as well as methods of treatment and therapeutic uses of the same.
Core Innovation
The patent describes amphotericin B (AmB) C16 hybrid amide derivatives of C2-epi-amphotericin B (C2-epiAmB) and pharmaceutically acceptable salts. It addresses limitations associated with AmB and C2-epiAmB by emphasizing improved therapeutic index, selective ergosterol binding, and reduced cholesterol binding.
The disclosure includes synthetic preparation of amide derivatives of C2-epi-AmB/Amphotericin B by amine coupling and purification of the resulting compounds, together with depicted structures for compounds and intermediates. It also includes pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers, and methods and uses for treating fungal infections using therapeutically effective amounts.
The compounds are reported as having antifungal activity and are evaluated for antifungal efficacy compared with Amphotericin B. Additional assessments address safety and DMPK-related parameters, including in vitro safety and tolerability such as hemolysis and renal markers, reduced renal toxicity biomarkers, in vivo efficacy and toxicity, PK, solubility evaluations, and characterization by NMR and LCMS.
Claims Coverage
The provided claim coverage centers on one compound claim group and associated use and composition claims, with six inventive features identified from the provided text.
Selected compound group or pharmaceutically acceptable salt
A compound selected from the group consisting of the disclosed compounds and a pharmaceutically acceptable salt thereof.
Treating a fungal infection by administering a therapeutically effective amount
A method of treating a fungal infection by administering a therapeutically effective amount of the compound of the selected compound group to a subject in need.
Intravenous administration for treating a fungal infection
The compound is administered intravenously in the method of treating the fungal infection.
Pharmaceutical composition comprising the compound with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound from the selected compound group together with a pharmaceutically acceptable carrier.
Oral dosage form pharmaceutical composition
The pharmaceutical composition is an oral dosage form.
Compound selected from the group
A compound selected from the group consisting of [group members not included in the provided partial text], or a pharmaceutically acceptable salt thereof.
The coverage includes amphotericin B C16 hybrid amide derivatives of C2-epiAmB or pharmaceutically acceptable salts, together with treatment of fungal infection and pharmaceutical composition claims. The provided dependent features further specify intravenous administration, a pharmaceutically acceptable carrier, and an oral dosage form.
Stated Advantages
Improved therapeutic index relative to limitations associated with AmB and C2-epiAmB.
Selective ergosterol binding.
Reduced mammalian (cholesterol) toxicity relative to AmB and C2-epiAmB.
Comparable and/or improved antifungal efficacy versus AmB, as reported by MIC data across yeasts and moulds.
Reduced cholesterol binding.
Reduced renal toxicity biomarkers (KIM1, LCN2, TIMP1, SPP1).
Documented Applications
Treating invasive fungal infections, including use against fungal pathogens referenced in the disclosure such as Candida and Aspergillus fumigatus.
Methods of treating a fungal infection using therapeutically effective doses, including intravenous and oral dosage forms.
Preclinical in vivo pulmonary aspergillosis efficacy/tolerance described in figure references.
Treatment of fungal infections, with in vivo models described as mouse candidiasis and mouse aspergillosis.
Antifungal evaluation against yeasts and moulds using MIC values.
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