Targeting liver nuclear receptors as a treatment for wilson disease

Patent metadata

Field	Value
Publication number	US-10583102-B2
Application number	US-201515517197-A
Country	US
Kind code	B2
Filing date	Oct 6, 2015
Priority date	Oct 6, 2014
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

The present invention relates to the field of Wilson Disease. More specifically, the present invention provides methods and compositions useful for treating Wilson Disease by targeting liver nuclear receptors. In a specific embodiment, a method for treating Wilson Disease in a subject comprises the step of administering to the subject an effective amount of a liver X receptor (LXR) agonist.

First claim

We claim:

1. A method for treating a patient suffering from Wilson Disease comprising the step of administering to the patient an effective amount of a liver X receptor (LXR) agonist.

2. The method of claim 1 , wherein the LXR agonist is a natural oxysterol, a synthetic oxysterol, a synthetic nonoxysterol or a natural nonoxysterol.

3. The method of claim 1 , wherein the LXR agonist is 20(S) hydroxycholesterol, 22(R) hydroxycholesterol, 24(S) hydroxycholesterol, 25-hydroxycholesterol, 24(S), 25 epoxycholesterol, 27-hydroxycholesterol, N,N-dimethyl-3β-hydroxycholenamide, N-(2,2,2-trifluoroethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1 (trifluoromethyl)ethyl]phenyl}benzene sulfonamide, [3-(3-(2-chloro-trifluoromethylbenzyl-2,2-diphenylethylamino)propoxy)phenylacetic acid], N-methyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-1-ethyl)phenyl]-benzenesulfonamide, 4,5-dihydro-1-(3-(3-trifluoromethyl-7-propyl-benzisoxazol-6-yloxy)propyl)-2,6-pyrimidinedione, 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-(4,5)-isoxazolyl)propylthio)-phenyl acetic acid, acetyl-podocarpic dimer, paxilline, desmosterol, or stigmasterol.

4. The method of claim 3 , wherein the LXR agonist is N-(2,2,2-trifluoroethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzene sulfonamide.

5. The method of claim 1 , wherein the LXR agonist is 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, or cholestenoic acid.

6. The method of claim 1 , wherein the LXR agonist is hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA).

7. A pharmaceutical composition comprising an LXR agonist and a copper chelator.

8. The composition of claim 7 , wherein the copper chelator is penicillamine, bathocuproine sulfonate, sodium diethyldithiocarbamate, trientine hydrochloride, or dimercaprol.

9. The composition of claim 7 , wherein the copper chelator is penicillamine or tientine hydrochloride.

10. A pharmaceutical composition comprising an LXR agonist and a metallothionein inducer.

11. The composition of claim 10 , wherein the metallothionein inducer is a zinc salt.

12. The composition of claim 11 , wherein the zine salt is zinc acetate.

13. A pharmaceutical composition comprising an LXR agonist and zine acetate.

14. A pharmaceutical composition comprising an LXR agonist, a copper chelator and a metallothionein inducer.

15. A pharmaceutical composition comprising an LXR agonist, a copper chelator and zinc acetate.

16. The method of claim 1 , further comprising administering to the patient an effective amount of a copper chelator.

17. The method of claim 16 , wherein the copper chelator is penicillamine, bathocuproine sulfonate, sodium diethyldithiocarbamate, trientine hydrochloride, dimercaprol or zinc acetate.

18. The method of claim 16 , wherein the copper chelator is penicillamine or tientine hydrochloride.

19. The method of claim 16 , further comprising administering to the patient an effective amount of a metallothionein inducer.

Assignees

• Univ Johns Hopkins

Inventors

• Lutsenko Svetlana
• Hamilton James

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/18 Primary

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K31/575

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title