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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• 作者：Anette Graven Sams ; Krestian Larsen ; Gitte Kobber?e Mikkelsen ; Morten Hentzer ; Claus Tornby Christoffersen ; Klaus Gjervig Jensen ; Kristen Frederiksen ; Benny Bang-Andersen
• 关键词：Schizophrenia ; Cognition ; D2 ; M1
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：22
• 期：15
• 页码：5134-5140
• 全文大小：717 K

文摘

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 D₂ receptor affinity and M₁ receptor agonism. Based on a strategy of controlling log P, we herein describe a hit-to-lead investigation with the aim of retaining the combined D₂/M₁ 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 D₂ receptor affinity by this effort; whilst it was feasible to obtain compounds with M₁ receptor agonism, acceptable clearance, and weak hERG inhibition.