Discovery of a Novel Alpha-7 Nicotinic Acetylcholine Receptor Agonist Series and Characterization of the Potent, Selective, and Orally Efficacious Agonist 5-(4-Acetyl[1,4]diazepan-1-yl)pentanoic Acid [5-(4-Methoxyphenyl)-1H-pyrazol-3-yl] Amide (SEN15924, WAY-361789)
| Autor: | Riccardo Zanaletti, John Dunlop, Flora Jow, Laura Maccari, Michela Valacchi, Iolanda Micco, Elisa Turlizzi, Cristiana Castaldo, Giovanni Gaviraghi, Simon N. Haydar, Giuseppe Cocconcelli, Thomas A. Comery, Chiara Ghiron, Laura Bettinetti, Carla Scali, Arianna Nencini |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Models Molecular Agonist ERG1 Potassium Channel Reflex Startle Cell Membrane Permeability Patch-Clamp Techniques alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Stereochemistry Administration Oral Alpha (ethology) Nicotinic Antagonists Receptors Nicotinic Pharmacology Cell Line Membrane Potentials Radioligand Assay Structure-Activity Relationship Cognition Dogs In vivo Catalytic Domain Drug Discovery medicine Animals Humans Structure–activity relationship Rats Long-Evans Nicotinic Agonists Receptor ADME Acetylcholine receptor Chemistry Brain Azepines Ether-A-Go-Go Potassium Channels Rats Nicotinic agonist Pyrazoles Molecular Medicine Calcium |
| Zdroj: | Journal of Medicinal Chemistry. 55:4806-4823 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating). |
| Databáze: | OpenAIRE |
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