1-[[4-Cyano-4-(2-methoxyphenyl)piperidin-1-yl]methyl]-4-oxoquinolizine-3-carboxylic acid | 1144504-44-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-[[4-Cyano-4-(2-methoxyphenyl)piperidin-1-yl]methyl]-4-oxoquinolizine-3-carboxylic acid
• CAS: 1144504-44-8
• 化学式: C₂₄H₂₃N₃O₄
• 分子量: 417.464
• InChiKey: RGPJQMQFIPCPTJ-UHFFFAOYSA-N

物化性质

• 沸点：
  713.5±60.0 °C(predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  93.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  邻甲氧基苯乙腈 在 盐酸 、 水 、 sodium hydride 、 溶剂黄146 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 乙腈 为溶剂， 反应 35.08h， 生成 1-[[4-Cyano-4-(2-methoxyphenyl)piperidin-1-yl]methyl]-4-oxoquinolizine-3-carboxylic acid
  参考文献：
  名称：

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

  摘要：

  One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M-1 muscarinic receptor. A number of nonselective M-1 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 M-2 to M-5 subtypes. One strategy to confer selectivity for M-1 is the identification of positive allosteric modulators, which would target an allosteric site on the M-1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have I been previously identified as highly selective M-1 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.

  DOI：

  10.1021/jm200400m

文献信息

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

  DOI：10.1021/jm200400m

  日期：2011.7.14

  One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M-1 muscarinic receptor. A number of nonselective M-1 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 M-2 to M-5 subtypes. One strategy to confer selectivity for M-1 is the identification of positive allosteric modulators, which would target an allosteric site on the M-1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have I been previously identified as highly selective M-1 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.