Discovery of a Selective Allosteric M1 Receptor Modulator with Suitable Development Properties Based on a Quinolizidinone Carboxylic Acid Scaffold

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• 作者：Scott D. Kuduk ; Ronald K. Chang ; Christina N. Di Marco ; Daniel R. Pitts ; Thomas J. Greshock ; Lei Ma ; Marion Wittmann ; Matthew A. Seager ; Kenneth A. Koeplinger ; Charles D. Thompson ; George D. Hartman ; Mark T. Bilodeau ; William J. Ray
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4773-4780
• 全文大小：860K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

One approach to ameliorate the cognitive decline in Alzheimer鈥檚 disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M₁ muscarinic receptor. A number of nonselective M₁ muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M₂ to M₅ subtypes. One strategy to confer selectivity for M₁ is the identification of positive allosteric modulators, which would target an allosteric site on the M₁ receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M₁ positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.