Gracilin A and congeners as immunosuppressive and neuroprotective agents

Patent metadata

Field	Value
Publication number	US-11066379-B2
Application number	US-201916977444-A
Country	US
Kind code	B2
Filing date	Mar 5, 2019
Priority date	Mar 5, 2018
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

Gracilin A congeners and methods for their use as immunosuppressive and neuroprotective agents.

First claim

The invention claimed is:

1. A method for suppressing an immune response in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

or a stereoisomer or racemate thereof, wherein:
R 1 , R 2 , and R 3 are independently H or C1-C3 alkyl, and the dashed line denotes a bond or an absence of a bond, with the proviso that only one dashed line is a bond.

2. The method of claim 1 , wherein the compound is:

or a stereoisomer or racemate thereof.

3. The method of claim 1 , wherein the compound is:

4. The method of claim 1 , wherein the subject has been diagnosed as suffering from an autoimmune disease or an inflammatory disease.

5. The method of claim 1 , wherein the compound inhibits interleukin-2 production.

6. The method of claim 5 , wherein the interleukin-2 production is inhibited by greater than about 20%.

7. The method of claim 1 , wherein the compound binds to CypA with a K D of less than about 6 μM.

8. The method of claim 1 , wherein the compound reduces T-cell viability in vitro by less than about 10%.

9. A method for treating a neurodegenerative disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

or a stereoisomer or racemate thereof, wherein:
R 1 , R 2 , and R 3 are independently H or C1-C3 alkyl;
R 4 is H, OH, OAc, or absent;
R 5 and R 8 are independently H or OAc;
R 6 and R 7 are H or R 6 and R 7 , taken together, are O; and
the dashed line denotes a bond when R 4 is absent, or absence of a bond when R 4 is H, OH, or OAc.

10. The method of claim 9 , wherein the compound is:

or a stereoisomer or racemate thereof.

11. The method of claim 9 , wherein the compound is:

12. The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease.

13. The method of claim 9 , wherein the compound inhibits CypD with an IC 50 of less than about 0.5 μM.

14. The method of claim 9 , wherein the compound inhibits CypA with an IC 50 of less than about 0.3 μM.

15. The method of claim 9 , wherein the compound inhibits CypD and does not inhibit CypA.

16. A compound having the formula:

or a stereoisomer or racemate thereof, wherein:
R 1 , R 2 , and R 3 are independently H or C1-C3 alkyl;
R 4 is H, OH, OAc, or absent;
R 5 and R 8 are independently H or OAc;
R 6 and R 7 , taken together, are O; and
the dashed line denotes a bond or absence of a bond with the proviso that only one dashed line is a bond, and with a further proviso that both dashed lines denote absence of a bond when R 4 is H, OH, or OAc.

17. The compound of claim 16 , wherein the compound is:

or a stereoisomer or racemate thereof.

18. The compound of claim 16 selected from the group consisting of:

19. A pharmaceutical composition, comprising a compound of claim 16 and a pharmaceutically acceptable carrier.

20. A method for suppressing an immune response in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

21. A compound having the formula:

22. A pharmaceutical composition, comprising a compound of claim 21 and a pharmaceutically acceptable carrier.

Assignees

• Texas A & M Univ Sys
• Univ Santiago Compostela

Inventors

• Romo Daniel
• Abbasov Mikail E
• Lopez Eva Alonso
• Alfonso Rancano Maria Amparo
• Botana Lopez Miguel Luis

Classifications

• A61P25/28 Primary

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• C07D307/88

  with one oxygen atom directly attached in position 1 or 3 · CPC title

• C07C69/16

  of dihydroxylic compounds · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title