Discovery of Diaryl Imidazolidin-2-one Derivatives, a Novel Class of Muscarinic M3 Selective Antagonists (Part 1)

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• 作者：Ilaria Peretto ; Roberto Forlani ; Claudia Fossati ; Giuseppe A. M. Giardina ; Alessandra Giardini ; Matilde Guala ; Elena La Porta ; Paola Petrillo ; Stefano Radaelli ; Luigi Radice ; Luca F. Raveglia ; Enza S
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 5, 2007
• 年：2007
• 卷：50
• 期：7
• 页码：1571 - 1583
• 全文大小：435K
• 年卷期：v.50,no.7(April 5, 2007)
• ISSN：1520-4804

文摘

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new classof muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatilityof the discovered scaffold allowed for several structural modifications that resulted in the discovery of twodistinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for thetreatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives(potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In thispaper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds,selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype ismainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor K_i = 4.8 nMand for M2 receptor K_i = 1141 nM. Functional in vitro studies on selected compounds confirmed theantagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.