Modulators of exchange proteins directly activated by cAMP (EPACS)

Patent metadata

Field	Value
Publication number	US-9539256-B2
Application number	US-201314377574-A
Country	US
Kind code	B2
Filing date	Feb 8, 2013
Priority date	Feb 10, 2012
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

Embodiments of the invention are directed to compounds that inhibit an activity of EP AC proteins and methods of using the same. The inventors have developed a sensitive and robust high throughput screening (HTS) assay for the purpose of identifying EPAC specific inhibitors (Tsalkova et al. (2012) PLOS ONE 7(1):e30441).

First claim

The invention claimed is:

1. An Exchange Protein Activated by cAMP (EPAC) specific inhibitor (ESI) having a formula of:

where W′ is a substituted or unsubstituted isoxazole and W″ is a 3-trifluoromethylphenyl; 3,5-di-trifluoromethylphenyl; 3-chlorophenyl; 2-chlorophenyl; 3,6-dichlorophenyl; 3,5-dichlorophenyl; 4-bromophenyl; 3-bromophenyl; 2,3-dichlorophenyl; or 3-chloro-4-hydroxyphenyl, wherein the compound is not 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

2. The EPAC specific inhibitor of claim 1 , wherein W′ is a C 1 to C 10 alkyl substituted isoxazole.

3. The EPAC specific inhibitor of claim 2 , wherein the substituted isoxazole is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, neo-pentyl, n-pentyl, or isopenyl substituted isoxazole.

4. The EPAC specific inhibitor of claim 1 , wherein W′ is a 5-methyl isoxazole or a 5-tert-butyl isoxazole.

5. The EPAC specific inhibitor of claim 1 , wherein the compound is selected from 3-(5-tert-Butyl-isoxazol-3-yl)-3-oxo-2-[(3-trifluoromethyl-phenyl)-hydrazono]propionitrile (HJC0720); 2-[(3,5-Bis-trifluoromethyl-phenyl)-hydrazono]-3-(5-tert-butyl-isoxazol-3-yl)-3-oxo-propionitrile (HJC0758); 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(2-chlorophenyl)-hydrazono]-3-oxo-propionitrile (HJC0693); 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(2,5-dichlorophenyl)-hydrazono]-3-oxo-propionitrile (HJC0696); 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3,5-dichlorophenyl)-hydrazono]-3-oxo-propionitrile (HJC0726); 2-[(4-Bromophenyl)-hydrazono]-3-(5-tert-butyl-isoxazol-3-yl)-3-oxo-propionitrile (HJC0742); 2-[(3-Bromophenyl)-hydrazono]-3-(5-tert-butyl-isoxazol-3-yl)-3-oxo-propionitrile (HJC0743); 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(2,3-dichlorophenyl)-hydrazono]-3-oxo-propionitrile (HJC0750); or 2-[(3,5-Dichlorophenyl)-hydrazono]-3-(5-methyl-isoxazol-3-yl)-3-oxo-propionitrile (HJC0770).

6. A pharmaceutically acceptable salt of the EPAC specific inhibitor of claim 1 .

7. A method for selectively inhibiting an EPAC protein comprising contacting the EPAC protein with 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09) or an EPAC specific inhibitor of claim 1 , wherein an activity of the EPAC protein is inhibited.

8. A method of treating cancer mediated by EPAC comprising administering an EPAC specific inhibitor to a subject having said cancer, wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09) or an EPAC specific inhibitor of claim 1 .

9. The method of claim 8 , wherein the EPAC specific inhibitor is selected from the EPAC specific inhibitors of claim 1 .

10. A method of enhancing an immune response to an antigen comprising administering an EPAC specific inhibitor to a subject exposed to the antigen, wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09) or an EPAC specific inhibitor of claim 1 .

11. The method of claim 10 , wherein the EPAC specific inhibitor is selected from the EPAC specific inhibitors of claim 1 .

12. A method of enhancing leptin sensitivity comprising administering an EPAC specific inhibitor to a subject having leptin resistance, wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09) or an EPAC specific inhibitor of claim 1 .

13. The method of claim 12 , wherein the EPAC specific inhibitor is selected form the EPAC specific inhibitors of claim 1 .

14. A method of suppressing bacteria, virus, or fungi infection comprising administering an EPAC specific inhibitor to a subject having a bacteria, virus, or fungi infection, wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09) or an EPAC specific inhibitor of claim 1 .

15. The method of claim 14 , wherein the EPAC specific inhibitor is selected from the EPAC specific inhibitors of claim 1 .

16. The EPAC specific inhibitor of claim 1 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3,5-dichlorophenyl)-hydrazono]-3-oxo-propionitrile (HJC0726).

17. The method of claim 7 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

18. The method of claim 8 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

19. The method of claim 9 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

20. The method of claim 12 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

21. The method of claim 14 , wherein the EPAC specific inhibitor is 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09).

Assignees

• Univ Texas

Inventors

• Cheng Xiaodong
• Zhou Jia
• Tsalkova Tamara
• Mei Fang
• Chen Haijun

Classifications

• A61P31/10

  Antimycotics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title