N-substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators.
A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, United Kingdom. Kevin.M.Thewlis@gsk.com
Kevin M
KM
Thewlis
Laura
L
Aldegheri
Mark H
MH
Harries
Claudette
C
Mookherjee
Beatrice
B
Oliosi
Simon E
SE
Ward
D002490:Central Nervous System / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020033:Protein Isoforms; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013449:Sulfonamides
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005663:Furans; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D011759:Pyrrolidines; D018091:Receptors, AMPA; D013449:Sulfonamides