TLR4 inhibitors for the treatment of human infectious and inflammatory disorders

• US 10,300,083 B2
• Filed: 12/19/2016
• Issued: 05/28/2019
• Est. Priority Date: 09/24/2010
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Wipf, Peter, Neal, Matthew D., Chhinder, Sodhi P., Hackam, David J.
• Primary Examiner(s): Lewis, Patrick T
• Application Number:
  US15/383,625
• Publication Number:
  US 20170095493A1
• Time in Patent Office: 890 Days
• Field of Search: None
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7024 Esters of saccharides
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin

Abstract

The present invention relates to methods of treating infectious, inflammatory and post-traumatic disorders by administering various compounds newly discovered to have TLR4 inhibitory activity. In addition to methods of treatment, the present invention further provides for pharmaceutical compositions comprising said compounds, together with a suitable pharmaceutical carrier. Because TLR4 is the most upstream receptor in the pro-inflammatory LPS signaling cascade, treatments of the invention, which inhibit or antagonize TLR4 action, may avoid the pitfalls associated with other cytokine inhibitors that act further down the pathway and accordingly play a less specific (and perhaps non-critical) role.

Claims

1. A method of treating an infectious or inflammatory disorder comprising administering, to a subject in need of such treatment, an effective amount of isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside that reduces one or more sign or symptom of inflammation in the subject.

2. The method of claim 1, wherein the subject is suffering from sepsis.

3. The method of claim 1, wherein the subject is suffering from arthritis.

4. The method of claim 1, wherein the isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside has the chemical structure:

5. A method of treating a disease or disorder involving TLR4activation comprising, administering to a subject in need of such treatment, an effective amount of isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside that reduces one or more sign or symptom of inflammation in the subject.

6. The method of claim 5, wherein the subject is suffering from an intestinal inflammatory disorder and the effective amount of isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside reduces intestinal inflammation in the subject.

7. The method of claim 6, wherein the subject is suffering from necrotizing enterocolitis.

8. The method of claim 6, wherein the subject is suffering from ulcerative colitis.

9. The method of claim 6, wherein the subject is suffering from Crohn'"'"'s disease.

10. The method of claim 5, wherein the subject is suffering from a cardiovascular disease and the effective amount of isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2- deoxyhexopyranoside reduces myocardial ischemia in the subject.

11. The method of claim 10, wherein the subject is suffering from angina.

12. The method of claim 10, wherein the subject has suffered a myocardial infarction.

13. The method of claim 10, wherein the subject is at increased risk of suffering a myocardial infarction.

14. The method of claim 5, wherein the subject is suffering from a traumatic injury and the effective amount of isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside reduces Toll-like receptor 4-induced post-traumatic injury.

15. The method of claim 14, wherein the traumatic injury is to an organ selected from the group consisting of the heart, the liver, the lung, the kidney, the intestine, the brain, the eye and the pancreas.

16. A pharmaceutical composition comprising isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside.

17. The pharmaceutical composition of claim 16, wherein the isopropyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxyhexopyranoside has the chemical structure:

18. The pharmaceutical composition of claim 16, further comprising an additional agent selected from the group consisting of an antibiotic agent, a steroid, a non-steroidal anti-inflammatory agent, an analgesic agent, an agent that improves cardiac function and/or reduces cardiac stress, an angiotensin converting enzyme inhibitor, a beta blocker, nitroglycerin, digoxin, a calcium channel blocker, and a combination thereof.