Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-11
2000-03-14
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31445
Patent
active
060373512
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a novel method of inhibiting hepatitis B virus and, more particularly, to the use of N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol for inhibiting replication and secretion of hepatitis B virus in cells infected with said virus.
Hepatitis B Virus (HBV) is a causative agent of acute and chronic liver disease [Ayoola et al., Bull. World Health Organ. 66, 443-455 (1988)]. Although effective vaccination is available [two HBV vaccines currently available are Merck's Recombivax HB and SmithKline Beecham's Engerix-B], there are still more than 300 million people worldwide chronically infected with the virus [Eder et al., in Progress in Liver Diseases, eds. Popper and Schaffner (Grune & Stratton, Orlando, FL), vol. 8, pp. 367-394 (1986)]. For them, the vaccine has no therapeutic value. According to Dr. Richard Duma, executive director of the National Foundation for Infectious Diseases, an estimated 300,000 cases of HBV infection occur annually in the United States alone [Med. World News 34(8), 20-21 (1993)]. Between 25 to 40% of those who are chronically infected with HBV develop serious liver disease. It is therefore important to find effective anti-HBV therapies.
Alpha interferon has been used for treatment of HBV infection with promising results in some patients [Hoofnagle and Jones, Seminars in Liver Disease 9, 231-233 (1989); and Perrillo, Seminars in Liver Disease 9, 240-248 (1989)]. The only treatment for chronic HBV infection currently approved by the U.S. FDA is recombinant interferon alfa-2b (Intron A, Schering-Plough). Clinical tests on the use of the nucleoside analog, fialuridine, for treatment of chronic hepatitis B were suspended recently due to drug-related liver failure in six of 20 patients. Consequently, there is a great need for a safe drug treatment of hepatitis B.
Recent reports suggest that the virus encoded DNA polymerase, which functions as a reverse transcriptase, is an attractive target [Doong et al., Proc. Natl. Acad. Sci. USA 88, 8495-8499 (1991); Lee et al., Antimicrob. Aaent Chem. 33, 336-339 (1989); Price et al., Proc. Natl. Acad. Sci. USA 86, 8541-8544 (1989); and Venkateswaran et al., Proc. Natl. Acad. Sci. USA 84, 274-278 (1987)].
Other virus-mediated processes have not been targeted for anti-viral intervention. Effective antiviral therapy for HBV is likely to involve multiple strategies, including agents that influence the host immune system as well as those that interfere with different steps in the life cycle of the virus. It is therefore of interest to explore the possibility that other, non-polymerase mediated steps in the virus life cycle are vulnerable to intervention.
1,5-Dideoxy-1,5-imino-D-glucitol (which is also known as 1-deoxynojirimycin or DNJ) and its N-alkyl derivatives are known inhibitors of the N-linked oligosaccharide processing enzymes, .alpha.-glucosidase I and II. Saunier et al., J. Biol. Chem. 257, 14155-14161 (1982); Elbein, Ann. Rev. Biochem. 56, 497-534 (1987). As glucose analogs they also have potential to inhibit glucosyl-transferases. Newbrun et al., Arch. Oral Biol. 28, 516-536 (1983); Wang et al., Tetrahedron Lett. 34, 403-406 (1993). Their inhibitory activity against the glucosidases has led to the development of these compounds as antihyperglycemic agents and antiviral agents. See, e.g., PCT Int'l. Appln. WO 87/03903 and U.S. Pat. Nos.: 4,065,562; 4,182,767; 4,533,668; 4,639,436; 4,849,430; 4,957,926; 5,011,829; and 5,030,638.
Studies on the effect of inhibitory agents on hepatitis B virus (HBV) have been sparse heretofore due to the lack of permissive cell culture systems for assay purposes. That is, the inability heretofore to reproduce and productively infect tissue cultures with the virus has been a serious limitation to the discovery of useful anti-HBV agents.
In one study, N-methyl deoxynojirimycin has been reported to inhibit the formation of mouse hepatitis virus (MHV) whereby the appearance of E2 on the cell surface is delayed. See Repp et al., J. Biol. Chem. 280, 15873-1587
REFERENCES:
patent: 4182767 (1980-01-01), Murai et al.
patent: 4849430 (1989-07-01), Fleet et al.
patent: 4957926 (1990-09-01), Jacob et al.
patent: 5030638 (1991-07-01), Partis et al.
Gerlich and Bruss, in Hepatitis B vaccines in Clinical Practice, ed. R.W. Ellis, Marcel Dekker, Inc., pp. 41-82, 1992.
Karpas et al., Proc. Natl. Acad. Sci. USA 85, pp. 9229-9233, 1988.
Repp et al., J. Biol. Chem. 260, pp. 15673-15679, 1985.
Datema et al., Pharmac. Ther. 33, 221, pp. 259-260, 1987.
Pizer et al., J. Virol. 34, pp. 142-153, 1980.
Sells et al., Proc. Natl. Acad. Sci. USA 84, pp. 1005-1009, 1987.
Gripon et al., Mol. Biol. HBv. San Diego, CA, Abst. 67, 1992.
Heerman et al., in Viral Hepatitis and Liver Disease, ed. Zuckerman A.R. Liss, pp. 697-700, 1988.
Heeman et al., J. Virol. 52, pp. 396-402, 1994.
Block et al., Proc. Natl. Acad. Sci. USA 91, 2235-2239 (1994).
Ganem, Chemtracts: Organic Chem.--7(2), 106-107 (1994).
Repp et al., J. Biol. Chem. 260, 15873-15879 (1985).
Niemann et al., Hoppe-Seyler's Zeitschrift Physiol. Chem.--365, p. 1040 (1984).
Kasambalides et al., J. Gen. Virol. 66, 2443-2451 (1985).
Karlsson et al., J. Biol. Chem.--268, 570-576 (1993).
Karpas et al., Proc. Natl. Acad. Sci. USA 85, 9229-9233 (1988).
Fleet et al., FEBS Lett. 237, 128-132 (1988).
Block Timothy M.
Blumberg Baruch S.
Dwek Raymond A.
G. D. Searle & Co.
Henley III Raymond
Meyer Scott J.
LandOfFree
Method of inhibiting hepatitis B virus does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of inhibiting hepatitis B virus, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of inhibiting hepatitis B virus will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-169461