SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist |
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Authors: | Simon N Haydar Chiara Ghiron Laura Bettinetti Hendrick Bothmann Thomas A Comery John Dunlop Salvatore La Rosa Iolanda Micco Martina Pollastrini Joanna Quinn Renza Roncarati Carla Scali Michela Valacchi Maurizio Varrone Riccardo Zanaletti |
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Institution: | 1. Chemical Sciences and Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA;2. Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy |
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Abstract: | Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer’s disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer’s disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed. |
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