Discovery of N-{1-[3-(3-Oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl] piperidin-4-yl}-2-phenylacetamide (Lu AE51090): An allosteric muscarinic M 1 receptor agonist with unprecedented selectivity and procognitive potential

Article abstract of DOI:10.1021/jm100697g

The discovery and Structure-activity relationship (SAR) of a series of allosteric muscarinic M₁ receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M₁ receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.