N-substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

Kevin M Thewlis; Laura Aldegheri; Mark H Harries; Claudette Mookherjee; Beatrice Oliosi; Simon E Ward

doi:10.1016/j.bmcl.2010.09.062

N-substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

Bioorg Med Chem Lett. 2010 Dec 1;20(23):7116-9. doi: 10.1016/j.bmcl.2010.09.062. Epub 2010 Sep 17.

Authors

Kevin M Thewlis¹, Laura Aldegheri, Mark H Harries, Claudette Mookherjee, Beatrice Oliosi, Simon E Ward

Affiliation

¹ Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, United Kingdom. Kevin.M.Thewlis@gsk.com

PMID: 20971003
DOI: 10.1016/j.bmcl.2010.09.062

Abstract

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.

MeSH terms

Central Nervous System / metabolism
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / drug effects
Furans / chemistry
Furans / pharmacology*
Humans
Protein Isoforms
Pyrrolidines / chemistry
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology*
Receptors, AMPA / drug effects*
Structure-Activity Relationship
Sulfonamides

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Furans
KCNH2 protein, human
Protein Isoforms
Pyrrolidines
Receptors, AMPA
Sulfonamides