GABAA agonists and methods of using to control airway hyperresponsiveness and inflammation in asthma
Novel methods of treating inflammation and airway constriction using GABAergic compounds with reduced benzo-diazepine-like CNS activity are provided. Novel compounds which selectively target alpha-4 and alpha-5 GABA A receptors and methods of using those compounds to treat bronchoconstriction and inflammation are provided herein.
1. A compound according to formula (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
R 3 is
X is —O—;
R 4 is selected from C 1-4 alkyl;
R 5 is selected from H or C 1-4 alkyl;
or R 4 and R 5 together form a 4- or 5-membered heterocyclic ring which is saturated or unsaturated; wherein the ring contains from 1-3 heteroatoms selected from O, N, S, Si, and P; and
R 8 is C 1-4 alkyl or C 3-4 cycloalkyl;
with the proviso that R 8 is not CH 3 when R 4 and R 5 are a C 2-3 alkylene chain and form a 4- or 5- membered ring.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 form the 4- or 5-membered heterocyclic ring.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein the ring contains 2-3 heteroatoms.
4. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein the ring has 5 member atoms.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 contains at least one deuterium ( 2 H) in place of a hydrogen.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt whereof, wherein R 8 contains at least one deuterium ( 2 H) in place of a hydrogen.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIA) or (IIB):
wherein
R 8 is -CD 3 , ethyl t-butyl or cyclopropyl;
R 3 is H; and
n is 1 or 2.
8. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A method of reducing airway constriction comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. A method of reducing lung inflammation comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.