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 or psychiatric disorder, the method comprising administering to the subject a compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of a bond, —O—, and —(CH 2 ) n —, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 1 is selected from the group consisting of C 1-6 alkyl and substituted C 1-6 alkyl;
R 2 is —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ;
R 2 ′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;
each R 3 and R 4 is independently H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, —(CR 3 R 4 ) m —NR 5 R 6 , or
m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 5 and R 6 is independently H or alkyl; and
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
in an amount effective to treat the cognitive deficit or psychiatric disorder.
2 . The method of claim 1 , wherein X is —CH 2 —.
3 . The method of claim 1 , wherein X is —O—.
4 . The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, trimethylammonium, triethylammonium, tri(hydroxyethyl)ammonium, tripropylammonium, and tri(hydroxypropyl)ammonium.
5 . The method of claim 1 , wherein:
m is 1;
each R 3 and R 4 are independently H, C 1 -C 6 alkyl, aryl or substituted aryl; and
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
6 . The method of claim 1 , wherein the compound having formula (I) is a compound having formula (II):
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.
7 . The method of claim 6 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
8 . The method of claim 6 , wherein R 3 is H and R 4 is selected from the group consisting of methyl and phenyl.
9 . The method of claim 6 , wherein R 10 is selected from the group consisting of isopropyl and tert-butyl.
10 . The method of claim 1 , wherein the compound having formula (I) is selected from the group consisting of
11 . The method of claim 10 , wherein the compound having formula (I) is selected from the group consisting of:
12 . The method of claim 1 for treating a subject having a cognitive deficit.
13 . The method of claim 12 , wherein the cognitive deficit is characterized by impairment of the mental processes of perception, learning, memory, judgment, and/or reasoning.
14 . The method of claim 12 , wherein the cognitive deficit is due to a viral infection.
15 . The method of claim 14 , wherein the cognitive deficit is due to the human immunodeficiency virus (HIV).
16 . The method of claim 15 , wherein the virus is latent.
17 . The method of claim 12 , wherein the cognitive deficit is selected from the group consisting of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND).
18 . The method of claim 12 , wherein the cognitive deficit is associated with a neurodegenerative disorder.
19 . The method of claim 12 , wherein the cognitive deficit is associated with a psychiatric disorder.
20 . The method of claim 12 , wherein the cognitive deficit is associated with multiple sclerosis.
21 . The method of claim 1 for treating a subject having a psychiatric disorder.