Treatment of neurodegenerative diseases through inhibition of HSP90
Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.
1. A method for treatment of neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound having structure:
wherein R is hydrogen, or a C 1 to C 10 alkyl, C 2 to C 10 alkynyl, or C 2 to C 10 alkoxyalkyl group, optionally including heteroatoms;
Y 1 and Y 2 are independently C or N;
X 4 is hydrogen or halogen;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl; and
X 2 is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkylm NH 2 , OH, or CN; and
X 1 has the formula —X—Y—Z— wherein, X, Y and Z are independently C, N, S or O, connected by single or double bonds and with apporpriate hydrogen substitution to satisfy valence, or Y may be (CH 2 ) 2 ,
wherein one of X and Z is bonded at the 5′-position to the aryl ring and the other is bonded to the 4′position, and wherein the compound is optionally in the form of an acid addition salt;
wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.
2. The method of claim 1 , wherein the compound and the mode of administration are selected such that the compound is delivered to the brain.
3. The method of claim 2 , wherein at least one of X, Y and Z is a carbon atom.
4. The method of claim 3 , wherein X 1 is —O—(CH 2 ) n —O—, wherein n is 1 or 2.
5. The method of claim 1 , wherein at least one of X, Y and Z is a carbon atom.
6. The method of claim 5 , wherein X 1 is —O—(CH 2 ) n —O—, wherein n is 1 or 2.
7. The method of claim 6 , wherein X 2 is halogen.
8. The method of claim 7 , wherein X 2 is Br or I.
9. The method of claim 6 , wherein R is an alkyl group containing a nitrogen heteroatom.
10. The method of claim 9 , wherein R is 3-isopropylaminopropyl, 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl.
11. The method of claim 10 , wherein R is 3-(methyl(prop-2-ynyl)amino)propyl.
12. The method of claim 10 , wherein R is 2-(isobutylamino)ethyl.
13. The method of claim 10 , wherein R is 2-(neopentylamino)ethyl.
14. The method of claim 10 , wherein R is 3-isopropylaminopropyl.
15. The method of claim 10 , wherein X 2 is halogen.
16. The method of claim 15 , wherein X 2 is Br or I.
17. The method of claim 6 , wherein X 4 is halogen.
18. The method of claim 17 , wherein X 2 is halogen.
19. The method of claim 18 , wherein X 2 is Br or I.
20. The method of claim 17 , wherein R is an alkyl group containing a nitrogen heteroatom.
21. The method of claim 20 , wherein R is 3-isopropylaminopropyl, 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl.
22. The method of claim 20 , wherein R is 3-(methyl(prop-2-ynyl)amino)propyl.
23. The method of claim 20 , wherein R is 2-(isobutylamino)ethyl.
24. The method of claim 20 , wherein R is 2-(neopentylamino)ethyl.
25. The method of claim 20 , wherein R is 3-isopropylaminopropyl.
26. The method of claim 20 , wherein X 2 is halogen.
27. The method of claim 26 , wherein X 2 is Br or I.
28. The method of claim 4 , wherein R is a terminal alkyne.
29. The method of claim 28 , wherein R is propynyl.
30. The method of claim 29 , wherein X 2 is halogen.
31. The method of claim 1 , wherein the compound has the formula: PUDZ8
or an acid addition salt thereof.
32. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
33. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
34. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
35. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
36. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
37. The method of claim 1 , wherein the compound has the formula
or an acid addition salt thereof.
38. The method of claim 4 , wherein the compound crosses the blood brain barrier.
39. The method of claim 2 , wherein the neurodegenerative disease is one in which aggregate, plaque or tangle formation occurs.
40. The method of claim 2 , wherein the neurodegenerative disease is Alzheimer's Disease.
41. The method of claim 1 , wherein the neurodegenerative disease is one in which aggregate, plaque or tangle formation occurs.
42. The method of claim 1 , wherein the neurodegenerative disease is Alzheimer's Disease.
43. A compound:
or an acid addition salt thereof.
44. A method for treatment of a neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of claim 43 ; wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA of Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familiar FTDP-17 syndromes, Parkinson's disease, and Huntington disease.
45. The method of claim 1 , wherein the neurodegenerative disease is one that is characterized by abnormalities in a signaling pathway and/or by aberrant neuronal protein folding.
46. The method of claim 1 , wherein the compound and the mode of administration are selected such that the compound is delivered to afflicted neurons characterized by the adnormalities in a signaling pathway and/pr by aberrant neuronal protein folding.
47. The method of claim 35 , wherein the neurodegenerative disease Alzheimer's Disease (AD).