TETRACYCLINE COMPOUNDS FOR TREATING NEURODEGENERATIVE DISORDERS
Tetracycline compounds for treating neurodegenerative disorders are disclosed herein. Also disclosed is a pharmaceutical composition comprising the tetracycline compounds, and a method for treating, preventing, or ameliorating neurodegenerative disorders or inflammation in a subject by administering the tetracycline compounds or a pharmaceutical composition thereof, either alone or in combination with a second therapeutic agent.
1 . A method for treating or preventing a neurodegenerative disorder in a subject, the method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt thereof, such that said neurodegenerative disorder is treated or prevented.
2 . The method of claim 1 , wherein the tetracycline compound is a compound of formula (I)
wherein:
R 1 , R 2 , R 3 and R 4 are each independently H or unsubstituted C 1 -C 6 alkyl; and
R 5 , R 5′ , R 6 and R 6′ are each independently H, hydroxyl, or unsubstituted C 1 -C 6 alkyl.
3 . The method of claim 2 , wherein the tetracycline compound is a compound of formula (Ia) or (Ib):
4 . The method of claim 3 , wherein the tetracycline compound is Compound 1:
5 . The method of claim 1 , wherein the neurodegenerative disorder is associated with inflammation of the brain.
6 . The method of claim 5 , wherein the neurodegenerative disorder is multiple sclerosis.
7 . The method of claim 5 , wherein the neurodegenerative disorder is autoimmune encephalomyelitis.
8 . The method of claim 1 , wherein the neurodegenerative disorder is a demyelination associated disorder.
9 . The method of claim 8 , wherein the demyelination associated disorder is multiple sclerosis.
10 . The method of claim 8 , wherein a dosage of the tetracycline compound effective for inhibiting demyelination is lower than a dosage of minocycline effective for achieving the same extent of demyelination inhibition.
11 . The method of claim 8 , wherein axon loss is inhibited.
12 . The method of claim 1 , wherein the neurodegenerative disorder is stroke.
13 . The method of claim 1 , wherein the neurodegenerative disorder is Fragile X Syndrome.
14 . A method for treating or preventing inflammation in a subject, the method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt thereof, such said inflammation is treated or prevented.
15 . The method of claim 14 wherein the tetracycline compound is a compound of formula (I)
wherein:
R 1 , R 2 , R 3 and R 4 are each independently H or unsubstituted C 1 -C 6 alkyl; and
R 5 , R 5′ , R 6 and R 6′ are each independently H, hydroxyl, or unsubstituted C 1 -C 6 alkyl.
16 . The method of claim 15 , wherein the tetracycline compound is a compound of formula (Ia) or (Ib):
17 . The method of claim 16 , wherein the tetracycline compound is Compound 1:
18 . The method of claim 14 , wherein MMP-9 activity is inhibited.
19 . The method of claim 14 , wherein TNFα is inhibited.
20 . The method of claim 14 , wherein nitric oxide production by macrophages is inhibited.
21 . A method for treating or preventing stroke in a subject, the method comprising administering to said subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, such that stroke is treated or prevented.
22 . A method for treating or preventing multiple sclerosis in a subject, the method comprising administering to said subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, such that multiple sclerosis is treated or prevented.
23 . A method for treating Fragile X Syndrome in a subject, the method comprising administering to said subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, such that Fragile X Syndrome is treated.
24 . The method of any one of claim 21 , 22 or 23 , wherein the subject is a human.
25 . The method of claim 1 , wherein the neurodegenerative disorder is treated with less tissue staining than caused by the same dose of minocycline.
26 . The method of claim 25 , wherein the neurodegenerative disorder is treated without substantial tissue staining.
27 . The method of claim 1 , wherein the neurodegenerative disorder is treated with lesser antibacterial effect than caused by the same dose of minocycline.
28 . The method of claim 27 , wherein the neurodegenerative disorder is treated without substantial antibacterial activity.
29 . The method of claim 26 or 28 , wherein the neurodegenerative disorder is multiple sclerosis.
30 . The method of claim 1 , wherein the neurodegenerative disorder is encephalomyelitis.