LYSINE DEMETHYLASE INHIBITORS FOR DISEASES AND DISORDERS ASSOCIATED WITH HEPADNAVIRIDAE

• US 20130095067A1
• Filed: 02/24/2011
• Published: 04/18/2013
• Est. Priority Date: 02/24/2010
• Status: Active Grant

• Current Assignee: Jonathan Alleman Baker, Matthew Colin Thor Fyfe
• Original Assignee: Jonathan Alleman Baker, Matthew Colin Thor Fyfe
• Inventors: Fyfe, Matthew Colin Thor, Baker, Jonathan Alleman
• Granted Patent: US 9,186,337 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/131 acyclic
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention provides for the treatment or prevention of Hepadnaviridae infection and disease caused by Hepadnaviridae infection. In particular, the invention provides compositions and methods that affect the ability of Hepadnaviridae to utilize the host'"'"'s cellular machinery as part of the virus'"'"' lifecycle. The invention relates to the discovery that interfering with the normal ability of viruses to utilize the host cell machinery with LSD1 inhibitors reduces HBV replication. Thus, the treatment and prevention of Hepadnaviridae infection and disease caused by Hepadnaviridae according to the invention comprises administering to an individual in need of treatment, a therapeutically effective amount of a LSD1 inhibitor. The individual in need of treatment can be a human or, e.g., another mammal.

Claims

1. A method of treating a Hepadnaviridae infection or a disease or disorder associated with Hepadnaviridae, the method comprising identifying an individual in need of such treatment and administering to the individual a LSD1 inhibitor.

2. The method according to claim 1, wherein the Hepadnaviridae infection is a Hepatitis B virus infection.

3. The method according to claim 1, wherein the Hepadnaviridae infection is a Hepatitis B virus infection resistant to one or more DNA polymerases inhibitors.

4. The method according to claim 1, wherein the LSD1 inhibitor is a reversible or irreversible amine oxidase inhibitor.

5. The method according to claim 1, wherein the LSD1 inhibitor inhibits Hepadnaviridae DNA replication.

6. The method according to claim 1, wherein the LSD1 inhibitor is a phenylcyclopropylamine derivative or analog, a phenelzine analog or derivative, or a propargylamine analog or derivative.

7. The method according to claim 1, wherein the LSD1 inhibitor has a therapeutic index of 10 or greater.

8. The method according to claim 1, wherein the LSD1 inhibitor has a therapeutic index of 20 or greater.

9. The method according to claim 2, further comprising administering to the individual a second anti-HBV agent.

10. The method according to claim 9, wherein the second anti-HBV agent is an interferon agent or a DNA polymerase inhibitor.

19. The method according to claim 6, wherein the phenelzine analog or derivative:

(a) has one, two, three, four or five substituents on the phenyl group;

(b) has the phenyl group substituted with (exchanged for) an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group has zero, one, two, three, four or five substituents;

or

(c) as in (a) or (b) and wherein the phenylzine analog or derivative has a substitution on the terminal nitrogen of the hydrazine group.

20. The method according to claim 6, wherein the propargylamine derivative or analog is a pargyline derivative or analog, and wherein:

(a) the pargyline derivative or analog has one, two, three, four or five substituents on the phenyl group;

(b) the pargyline derivative or analog has the phenyl group substituted with (exchanged for) an aryl or heterocyclyl group wherein the aryl or heterocyclyl group has zero, one, two, three, four or five substituents;

or

(c) as in (a) or (b) and wherein the propargylamine moiety of pargyline has one or two substituents.

21. The method according to claim 6, wherein the phenylcyclopropylamine derivative or analog:

(a) has one, two, three, four or five substituents on the phenyl group;

(b) has the phenyl group substituted with (exchanged for) an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group has zero, one, two, three, four or five substituents;

or

(c) as in (a) or (b) and wherein the phenycyclopropylamine derivative or analog has one or two substituents on the amino group of the cyclopropylamine core.

11-18. -18. (canceled)

22. A method of treating HBV and HCV co-infection, the method comprising identifying an individual in need of such treatment and administering to the individual a LSD1 inhibitor.

23. The method according to claim 22, wherein the LSD1 inhibitor has a therapeutic index of 10 or greater.

24. The method according to claim 22, further comprising administering to the individual a second anti-HCV agent or anti-HBV agent.