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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| Affiliation: | 1. Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark;2. Department of Pharmacology, University of Florida College of Medicine, Gainesville, FL, USA;1. Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany;2. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany;3. H. Lundbeck A/S, Valby, Denmark;4. Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, USA;5. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA;6. Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA;1. Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, United States;2. Research Service, San Diego Veteran''s Affairs Hospital, 3350 La Jolla Drive, San Diego, CA 92037, United States;3. NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark;4. Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;5. Faculty of Pharmacy, A15, The University of Sydney, New South Wales 2006, Australia;6. Aniona ApS, Baltorpvej 154, 2750 Ballerup, Denmark |
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| 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). |
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| Keywords: | Nicotinic acetylcholine receptors Positive allosteric modulator Electrophysiology Lead optimization Novel object recognition |
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