Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential |
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Authors: | Sams Anette Graven Larsen Krestian Mikkelsen Gitte Kobberøe Hentzer Morten Christoffersen Claus Tornby Jensen Klaus Gjervig Frederiksen Kristen Bang-Andersen Benny |
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Affiliation: | Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, Copenhagen-Valby, Denmark. anette.sams@leo-pharma.com |
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Abstract: | We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition. |
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