Referenced in: none

Automatically associated channels: TASK1

Title: Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allosteric modulator of alpha-7 nicotinic acetylcholine receptors: attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral ad

Authors: Jørgen Eskildsen, John P Redrobe, Anette G Sams, Kim Dekermendjian, Morten Laursen, Jette B Boll, Roger L Papke, Christoffer Bundgaard, Kristen Frederiksen, Jesper F Bastlund

Journal, date & volume: Bioorg. Med. Chem. Lett., 2014 Jan 1 , 24, 288-93

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24291041

Abstract
In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure-activity relationships for α7 PAM potency, intrinsic hepatic clearance, the structure-property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the α7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).