Activators of class I histone deacetylases (HDACs) and uses thereof
The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D).
1. A method for therapeutically treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (C-III):
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:
each instance of R C1 and R C2 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C2a , —N(R C2b ) 2 , —SR C2a , —C(═O)R C2a , —C(═O)OR C2a , —C(═O)SR C2a , —C(═O)N(R C2b ) 2 , —OC(═O)R C2b , —OC(═O)OR C2a , —OC(═O)SR C2b , —OC(═O)N(R C2b ) 2 , —NR C2b C(═O)R C2b , —NR C2b C(═O)OR C2a , —NR C2b C(═O)SR C2a , —NR C2b C(═O)N(R C2b ) 2 , —SC(═O)R C2a , —SC(═O)OR C2a , —SC(═O)SR C2b , —SC(═O)N(R C2b ) 2 , —C(═NR C2b )R C2a , —C(═NR C2b )OR C2a , —C(═NR C2b )SR C2a , —C(═NR C2b )N(R C2b ) 2 , —OC(═NR C2b )R C2a , —OC(═NR C2b )OR C2a , —OC(═NR C2b )SR C2a , —OC(═NR C2b )N(R C2b ) 2 , —NR C2b C(═NR C2b )R C2b , —NR C2b C(═NR C2b )OR C2a , —NR C2b C(═NR C2b )SR C2a , —NR C2b C(═NR C2b )N(R C2b ) 2 , —SC(═NR C2b )R C2a , —SC(═NR C2b )OR C2a , —SC(═NR C2b )SR C2a , —SC(═NR C2b )N(R C2b ) 2 , —C(═S)R C2a , —C(═S)OR C2a , —C(═S)SR C2a , —C(═S)N(R C2b ) 2 , —OC(═S)R C2a , —OC(═S)OR C2a , —OC(═S)SR C2a , —OC(═S)N(R C2b ) 2 , —NR C2b C(═S)R C2b , —NR C2b C(═S)OR C2a , —NR C2b C(═S)SR C2a , —NR C2b C(═S)N(R C2b ) 2 , —SC(═S)R C2a , —SC(═S)OR C2b , —SC(═S)SR C2a , —SC(═S)N(R C2b ) 2 , —S(═O)R C2a , —SO 2 R C2a , —NR C2b SO 2 R C2a , —SO 2 N(R C2b ) 2 , —CN, —SCN, and —NO 2 ,
wherein each occurrence of R C2a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R C2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R C2b groups are joined to form an optionally substituted heterocyclic ring;
q is 0, 1, 2, 3, or 4; and
r is 0, 1, 2, 3, 4, or 5.
2. The method in claim 1 , wherein the therapeutically effective amount is further effective in activating class I histone deacetylase.
3. The method in claim 1 , wherein the therapeutically effective amount is further effective in activating histone deacetylase 1.
4. The method in claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
5. The method of claim 1 , wherein the neurological disorder is Alzheimer's disease.
6. The method of claim 1 , wherein the neurological disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic brain injury, stroke, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion disease, Niemann Pick disease type C, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosum, or Bloom syndrome.
7. The method of claim 1 , wherein the neurological disorder is frontal temporal dementia.
8. The method of claim 1 , wherein the neurological disorder is Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, or Kuru.
9. The method of claim 1 , wherein the neurological disorder is spinal cerebellar ataxia.
10. The method of claim 1 , wherein the compound is not:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
12. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
13. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:
each instance of R C3 and R C4 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C4a , —N(R C4b ) 2 , —SR C4a , —C(═O)R C4a , —C(═O)OR C4a , —C(═O)SR C4a , —C(═O)N(R C4b ) 2 , OC(═O)R C4a , —OC(═O)OR C4a , OC(═O)SR C4a , —OC(═O)N(R C4b ) 2 , —NR C4b C(═O)R C4b , —NR C4b C(═O)OR C4a , —NR C4b C(═O)SR C4a , —NR C4b C(═O)N(R C4b ) 2 , —SC(═O)R C4a , —SC(═O)OR C4a , —SC(═O)SR C4a , —SC(═O)N(R C4b ) 2 , —C(═NR C4b )R C4a , —C(═NR C4a )OR C4a , —C(═NR C4b )SR C4a , —C(═NR C4b )N(R C4b ) 2 , —OC(NR C4b )R C4a , —OC(═NR C4b )OR C4a , —OC(═NR C4b SR C4a , —OC(═NR C4b )N(R C4b ) 2 , —NR C4b C(═NR C4b )R C4b , —NR C4b C(═NR C4b )OR C4a , —NR C4b C(═NR C4b )SR C4a , —NR C4b C(═NR C4b )N(R C4b ) 2 , —SC(═NR C4b )R C4a , —SC(═NR C4b )OR C4a , —SC(═NR C4b )SR C4a , —SC(═NR C4b )N(R C4b ) 2 , —C(═S)R C4a , —C(═S)OR C4a , —C(═S)SR C4a , —C(═S)N(R C4b ) 2 , —OC(═S)R C4a , —OC(═S)OR C4a , —OC(═S)SR C4a , —OC(═S)N(R C4b ) 2 , —NR C4b C(═S)R C4b , —NR C4b C(═S)OR C4a , —NR C4b C(═S)SR C4a , —NR C4b C(═S)N(R C4b ) 2 , —SC(═S)R C4a , —SC(═S)OR C4a , —SC(═S)SR C4a , —SC(═S)N(R C4b ) 2 , —S(═O)R C4a , —SO 2 R C4a , —NR C4b SO 2 R C4a , —SO 2 N(R C4b ) 2 , —CN, —SCN, and —NO 2 ,
wherein each occurrence of R C4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R C4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R C4b groups are joined to form an optionally substituted heterocyclic ring; and
v is 0, 1, 2, and 3.
14. The method of claim 13 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
15. The method of claim 13 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
16. The method of claim 13 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
17. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
18. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
19. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
20. The method of claim 1 , wherein in the compound of Formula (C-III), at least one instance of R C1 is optionally substituted alkyl.
21. The method of claim 1 , wherein in the compound of Formula (C-III), at least one instance of R C2 is —OR C2a .
22. The method of claim 1 , wherein the neurological disorder is Parkinson's disease.
23. The method of claim 1 , wherein the neurological disorder is Huntington's disease.
24. The method of claim 1 , wherein the neurological disorder is amyotrophic lateral sclerosis.
25. The method of claim 1 , wherein the neurological disorder is stroke.