Use of amphotericin B derivatives as protease inhibitors

Details Use of amphotericin B derivatives as protease inhibitors Use of amphotericin B derivatives as protease inhibitors

1993-11-15

1996-05-07

Robinson, Douglas W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

424118, 424119, 536 65, 536115, 549269, 549270, A61K 3170

Patent

active

055146627

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of derivatives of polyene macrolides, in particular amphotericin B, as protease inhibitors, and to the applications of said inhibitors for the production of medicinal products intended in particular for the treatment of infection by the human immunodeficiency virus (HIV).
Since the identification of HIV-1 and HIV-2 as agents for AIDS, numerous research studies have been carried out with the aim of understanding the mechanism of viral infection and of obtaining effective antiviral treatments.
Until now, nucleoside analogues such as AZT (3'-azido-2',3'-dideoxythymidine) and ddI (2',3'-dideoxyinosine) have been used for the treatment of AIDS and have resulted in an improvement of the clinical condition of patients. Unfortunately, severe side effects of treatment with AZT, in particular a degeneration of bone marrow, have been reported, and moreover, many patients do not tolerate the drug very well or they become insensitive to its beneficial effects.
In the case of ddI, its use is still only at the experimental stage and its efficacy requires further investigation.
Furthermore, it has been shown that amphotericin B (AmB) and some of its derivatives are active in vitro against several DNA and RNA viruses containing a lipid envelope, and against various herpes virus strains. The methyl ester of amphotericin B (AME) SCHAFFNER et al., Biochem. Pharm., 35, 4110-4113, 1986! as well as liposome-encapsulated amphotericin B PONTANI et al., Antiviral. Res. 11, 119-126 (1989)! have also been described as inhibitors of cell death and of viral expression in T cells infected in vitro with HIV-1. Moreover, since it is known that amphotericin B and its derivatives interact with cellular membrane cholesterol, which causes fluidification of said membranes, it was assumed that this mechanism was responsible for their antiviral activity, either by destroying the virus or by preventing its penetration into the target cells. HANSEN et al. Antiviral Research, 14, 149-160, (1990)! have studied the in vitro activity of various amphotericin derivatives on the HIV-1 virus. According to the results of this study, AME acts as a cell protecting agent by inhibiting the infection of cells by free HIV: incubation of healthy lymphocytes in the presence of AME prior to infection in vitro with an HIV isolate inhibits the infection; on the other hand, when HIV-infected lymphocytes are preincubated in the presence of AME, their capacity to fuse with uninfected cells so as to form syncytia is increased. Another of the derivatives studied, MCG {N N'-(2,4'-methylmorpholino)-N"-ethylguanyl!amphotericin B}, does not possess, according to this study, cell-protecting properties, but has a direct antiviral action: in the case of MCG, it is the preincubation with the virus and not with the cells which inhibits vital infection.
Amphotericin B is currently used in patients suffering from AIDS, in the treatment of infections caused by opportunistic microbes, in particular of deep-rooted mycoses which frequently occur in these patients. Clinical studies have shown that an antifungal therapy has to be maintained indefinitely in order to avoid relapses, or even used as a preventive measure. However, frequent side effects such as fever or serious nephrotoxicity are associated with prolonged treatment using amphotericin B.
By seeking out more active antifungal agents having a reduced toxicity and an enhanced efficacy, the inventors recently obtained, by substituting the mycosamine functional group of amphotericin B by a 1-amino-1-deoxyketose which can itself be substituted, a series of new derivatives which are more soluble and less toxic than amphotericin B; these derivatives and their use as antifungal agents are the subject of European Patent Application No. 428 440.
In fact, the inventors have now tested the action of some of these derivatives of formula (I) below ##STR1## in which: R1 represents the macrocyclic portion of the polyene macrolide,
They have thus observed that these derivatives inhibit the cytopathogenic

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Bstracts. STN International, Karlsruhe. AN=CA87(25):193736x. L. S. Kravchenko: "Study of the Proteolytic Activity of Lysosomes from Dog Kidneys Under the Effect of Amphotericin B In Vitro".

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