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 administration

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):288-93. doi: 10.1016/j.bmcl.2013.11.022.
Jørgen Eskildsen  1 ,  John P Redrobe  2 ,  Anette G Sams  2 ,  Kim Dekermendjian  2 ,  Morten Laursen  2 ,  Jette B Boll  2 ,  Roger L Papke  3 ,  Christoffer Bundgaard  2 ,  Kristen Frederiksen  2 ,  Jesper F Bastlund  2
Affiliations
  • 1. Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: [email protected].
  • 2. Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • 3. Department of Pharmacology, University of Florida College of Medicine, Gainesville, FL, USA.
PMID: 24291041 DOI: 10.1016/j.bmcl.2013.11.022
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).

Keywords
Electrophysiology; Lead optimization; Nicotinic acetylcholine receptors; Novel object recognition; Positive allosteric modulator.
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