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 administration.
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).
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: JORE@lundbeck.com.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Eskildsen
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: John P
authors.initials: JP
authors.lastname: Redrobe
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Anette G
authors.initials: AG
authors.lastname: Sams
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Dekermendjian
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Laursen
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Jette B
authors.initials: JB
authors.lastname: Boll
authors.affiliation: Department of Pharmacology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Kristen
authors.initials: K
authors.lastname: Frederiksen
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010622:Phencyclidine / Q000008:administration & dosage; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D003521:Cyclopropanes; C000588469:Lu AF58801; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010622:Phencyclidine; D010626:Phenylethyl Alcohol
keywords: Electrophysiology; Lead optimization; Nicotinic acetylcholine receptors; Novel object recognition; Positive allosteric modulator