Metabotropic glutamate receptor positive allosteric modulators (PAMS) and uses thereof
Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor positive allosteric modulators (PAMS), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (III):
wherein:
R 1 is —OH, —OR 4 , —NHOR 5 , —NHSO 2 R 4 , —NR 4 R 5 , or R 4 ;
or —C(═O)R 1 is a carboxylic acid bioisostere having the structure
Ring A is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
Ring B is substituted or unsubstituted 6-membered heteroaryl;
L 2 is absent or —O—(C 1 -C 6 alkylene);
R 2 is hydrogen, halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
Z is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
R 4 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
or R 4 and R 5 taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl;
n is 0, 1, 2, 3, 4; and
p is 0 or 1.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is —OH, —OR 4 , halogen, or substituted or unsubstituted C 1 -C 6 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L 2 is absent or —O—(CH 2 )—.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Ring A is substituted or unsubstituted aryl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Ring B is selected from a group consisting of:
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
p is 0 and n is 0.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
p is 1 and n is 0.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —OH, —OCH 3 , —OCH 2 CH 3 , or —NR 4 R 5 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen, halogen, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or solvate thereof, and at least one pharmaceutically acceptable excipient.
14. A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, in a subject in need thereof, the method comprising the step of administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method of treating an addictive disorder in a subject in need thereof, the method comprising the step of administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.