Methods of drug delivery to hepatocytes and treatment of flaviviridae infections

• US 20040077563A1
• Filed: 11/28/2003
• Published: 04/22/2004
• Est. Priority Date: 08/21/2001
• Status: Abandoned Application

• Current Assignee: Valeant Research & Development (Bausch Health Cos., Inc.)
• Original Assignee: Valeant Research & Development (Bausch Health Cos., Inc.)
• Inventors: Hong, Zhi, Lau, Johnson
• Application Number:
  US10/333,699
• Publication Number:
  US 20040077563A1
• Time in Patent Office: Days
• US Class Current: 514/42
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A method of delivering a drug to a hepatocyte includes a step in which a carboxamidine group-containing compound is provided to a hepatocyte having a transporter that transports the compound across the plasma membrane of the hepatocyte, wherein the transport of the compound is substantially not inhibited by ribavirin. Further contemplated methods include a method of inhibiting growth of a virus of a family of flaviviridae in a cell containing system, in which contemplated compounds are presented to a cell in the cell containing system.

Claims

1. A method of delivering a drug to a hepatocyte, comprising:

providing a compound having a carboxamidine group wherein the compound has an activity selected from the group consisting of anti-viral activity and anti-neoplastic activity;

ascertaining that the hepatocyte comprises a transporter that transports the compound across a plasma membrane of the hepatocyte wherein the transport of the compound is substantially not inhibited by ribavirin; and

presenting the transporter with the compound.

2. The method of claim 1, wherein the compound comprises a nucleoside having a base coupled to a sugar.

3. The method of claim 2, wherein the base comprises a monocyclic base.

4. The method of claim 3, wherein the monocyclic base comprises a 1,2,4-triazole.

5. The method of claim 2, wherein the sugar comprises a β

-ribofuranose.

6. The method of claim 2, wherein the nucleoside comprises 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine.

7. The method of claim 2, wherein the nucleoside comprises 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine.

8. The method of claim 1, wherein the carboxamidine group is converted to a carboxamide group in the hepatocyte.

9. The method of claim 8, wherein the carboxamide group is enzymatically phosphorylated and thereby accumulates in the hepatocyte.

10. The method of claim 1, wherein the anti-viral activity is an anti-viral activity against flaviviridae.

11. The method of claim 10, wherein the anti-viral activity against flaviviridae is an anti-viral activity against a pestivirus and a hepa C virus.

12. The method of claim 1, wherein the anti-neoplastic activity includes an anti-neoplastic activity against neoplastic hepatocytes.

13. The method of claim 1, wherein the transporter comprises an ATP-dependent transporter.

14. The method of claim 1, wherein the transporter comprises a transmembrane protein.

15. The method of claim 1, wherein the hepatocyte is diseased.

16. The method of claim 1, wherein transport of the compound comprises transport that is inhibited by a second compound having a carboxamidine group.

17. A method of inhibiting replication of a virus belonging to a family of flaviviridae in a cell containing system comprising:

providing a pharmaceutical composition having a carboxamidine group; and

presenting a cell in the cell containing system with the pharmaceutical composition, wherein the compound is transported across a plasma membrane of the cell, wherein the transport of the compound is substantially not inhibited by ribavirin.

18. The method of claim 17, wherein the virus is a West Nile virus.

19. The method of claim 17, wherein the virus is a hepatitis C virus.

20. The method of claim 17, wherein the cell containing system is an in vitro system.

21. The method of claim 17, wherein the cell containing system is an in vivo system.

23. The method of claim 17, wherein the pharmaceutical compound comprises 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine*HCl

24. The method of claim 17, wherein the pharmaceutical compound is in L-configuration.

22. The method of claim 22, wherein the in vivo system has at least one hepatocyte that is infected with the virus.