Amphotericin B derivative with reduced toxicity

Patent metadata

Field	Value
Publication number	US-9738677-B2
Application number	US-201515310815-A
Country	US
Kind code	B2
Filing date	May 15, 2015
Priority date	May 16, 2014
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Disclosed is a derivative of amphotericin B (AmB), denoted C2′epiAmB, with an improved therapeutic index over amphotericin B, pharmaceutical compositions comprising the AmB derivative, methods of making the AmB derivative and the pharmaceutical composition, and their use in methods of inhibiting growth of a yeast or fungus and treating a yeast or fungal infection. C2′epiAmB is an epimer of the parent compound. Specifically, C2′epiAmB differs from the parent compound at the C2′ stereogenic center on mycosamine. This difference in structure results in (i) retained capacity to bind ergosterol and inhibit growth of yeast, (ii) greatly reduced capacity to bind cholesterol, and (iii) essentially no toxicity to human cells.

First claim

We claim:

1. C2′epiAmB, represented by

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition, comprising the compound of claim 1 ;
and a pharmaceutically acceptable carrier.

3. A method of inhibiting growth of a yeast or fungus, comprising contacting the yeast or fungus with an effective amount of C2′epiAmB, represented by

or a pharmaceutically acceptable salt thereof.

4. A method of treating a yeast or fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of C2′epiAmB, represented by

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 , wherein the administration is topical.

6. The method of claim 4 , wherein the administration is systemic.

7. The method of claim 4 , wherein the administration is oral.

8. The method of claim 4 , wherein the administration is intravenous.

9. The method of claim 4 , wherein the administration is intramuscular.

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Uno Brice E

Classifications

• A61P31/10

  Antimycotics · CPC title

• C07H17/08 Primary

  Hetero rings containing eight or more ring members, e.g. erythromycins · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title