Chemical inhibition of the E3 ligase subunit FBXO7 confers neuroprotection and anti-inflammatory activity by stabilizing mitochondria
A method for treating a neurodegenerative disease or an inflammatory disorder in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II: wherein each of R 3 -R 7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy; R 8 is an optionally-substituted heterocycloalkyl; and a is 0 to 3.
1. A method for treating a neurodegenerative disease or an inflammatory disorder in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II:
wherein each of R 3 -R 7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy;
R 8 is an optionally-substituted heterocycloalkyl; and
a is 0 to 3.
2. The method of claim 1 , wherein the compound is:
3. A method for treating frontotemporal dementia, a mitochondrial disease caused by mutations in nuclear DNA, a mitochondrial disease caused by mutations in mtDNA, or a disease of skeletal or cardiac muscle in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II:
wherein each of R 3 -R 7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy;
R 8 is an optionally-substituted heterocycloalkyl; and
a is 0 to 3.
4. The method of claim 1 , wherein the subject is in need of treatment for Parkinson's disease and the compound is:
5. The method of claim 1 , wherein the subject is need of treatment for a neurodegenerative disease.
6. The method of claim 1 , wherein at least one of R 3 -R 7 is an aminoalkyl.
7. The method of claim 1 , wherein the aminoalkyl is —(CH 2 ) b —NR 9 R 10 , wherein R 9 and R 10 are each independently H or alkyl and b is 1 to 5.
8. The compound of claim 1 , wherein at least one of R 3 -R 7 is an amino.
9. The method of claim 8 , wherein the amino is —NH 2 or an alkylamino.
10. The method of claim 9 , wherein the alkylamino is —NR 11 R 12 , wherein R 11 and R 12 are each independently H or alkyl.
11. The method of claim 1 , wherein at least one of R 3 -R 7 is an alkoxy.
12. The method of claim 1 , wherein R 5 is not H.
13. The method of claim 1 , wherein R 5 is alkoxy or alkylamino.
14. The method of claim 1 , wherein at least two of R 3 -R 7 are halogen.
15. The method of claim 1 , wherein at least one of R 3 -R 7 is not H.
16. The method of claim 1 , wherein each of R 3 -R 7 is H.
17. The method of claim 1 , wherein R 8 is a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl.
18. The method of claim 1 , wherein R 8 is a heterocycloalkyl that includes at least one oxygen heteroatom.
19. The compound of claim 1 , wherein the heterocycloalkyl is selected from oxetanyl, dioxetanyl, oxolanyl, dioxolanyl, oxanyl or dioxanyl.
20. The method of claim 1 , wherein the heterocycloalkyl is oxolanyl or oxanyl.
21. The method of claim 1 , wherein R 8 is: