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
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 struct...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-01, Vol.24 (1), p.288-293 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Eskildsen, Jørgen Redrobe, John P Sams, Anette G Dekermendjian, Kim Laursen, Morten Boll, Jette B Papke, Roger L Bundgaard, Christoffer Frederiksen, Kristen Bastlund, Jesper F |
| description | 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). |
| doi_str_mv | 10.1016/j.bmcl.2013.11.022 |
| format | Article |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Allosteric Regulation - drug effects alpha7 Nicotinic Acetylcholine Receptor - metabolism Animals Brain - drug effects Brain - metabolism Cognition Disorders - chemically induced Cognition Disorders - drug therapy Cyclopropanes - administration & dosage Cyclopropanes - chemistry Cyclopropanes - pharmacology Dose-Response Relationship, Drug Drug Discovery Humans Molecular Structure Phencyclidine - administration & dosage Phenylethyl Alcohol - administration & dosage Phenylethyl Alcohol - analogs & derivatives Phenylethyl Alcohol - chemistry Phenylethyl Alcohol - pharmacology Rats Rats, Inbred Strains Structure-Activity Relationship |
| 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 |
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