Glutamine antagonists for the treatment of cognitive deficits and psychiatric disorders
The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification, for use in treating cognitive deficits and/or psychiatric disorders, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND). Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
1. A method for treating a subject having a cognitive deficit, the method comprising administering to the subject a compound having formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, and substituted aryl; and
R 10 is C 1-6 alkyl,
in an amount effective to treat the cognitive deficit.
2. The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
3. The method of claim 1 , wherein R 3 is H and R 4 is selected from the group consisting of methyl and phenyl.
4. The method of claim 1 , wherein R 10 is selected from the group consisting of isopropyl and tert-butyl.
5. The method of claim 1 , wherein the compound having formula (II) is selected from the group consisting of:
6. The method of claim 5 , wherein the compound having formula (I) is selected from the group consisting of:
7. The method of claim 1 , wherein the cognitive deficit is characterized by impairment of the mental processes of perception, learning, memory, judgment, and/or reasoning.
8. The method of claim 1 , wherein the cognitive deficit is due to a viral infection.
9. The method of claim 8 , wherein the cognitive deficit is due to the human immunodeficiency virus (HIV).
10. The method of claim 9 , wherein the virus is latent.
11. The method of claim 1 , wherein the cognitive deficit is selected from the group consisting of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND).
12. The method of claim 1 , wherein the cognitive deficit is associated with a neurodegenerative disorder.
13. The method of claim 1 , wherein the cognitive deficit is associated with multiple sclerosis.