1-isopentyl-2-oxo-4-(4-benzylpiperazin-1-yl)pyridine-3-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-isopentyl-2-oxo-4-(4-benzylpiperazin-1-yl)pyridine-3-carbonitrile
• 英文别名: 4-(4-Benzylpiperazin-1-yl)-1-(3-methylbutyl)-2-oxopyridine-3-carbonitrile；4-(4-benzylpiperazin-1-yl)-1-(3-methylbutyl)-2-oxopyridine-3-carbonitrile
• 化学式: C₂₂H₂₈N₄O
• 分子量: 364.491
• InChiKey: BUGHISOIHFLLOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  50.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-Isopentyl-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile 在 potassium phosphate 、 2-(2^'-di-tert-butylphosphine)biphenylpalladium(II) acetate 、 水 、 sodium hydroxide 、 三溴氧磷 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 1-isopentyl-2-oxo-4-(4-benzylpiperazin-1-yl)pyridine-3-carbonitrile
  参考文献：
  名称：

  Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

  摘要：

  We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.

  DOI：

  10.1021/jm500496m

文献信息

• Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1<i>H</i>)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor
  作者：José María Cid、Gary Tresadern、Guillaume Duvey、Robert Lütjens、Terry Finn、Jean-Philippe Rocher、Sonia Poli、Juan Antonio Vega、Ana Isabel de Lucas、Encarnación Matesanz、María Lourdes Linares、José Ignacio Andrés、Jesús Alcazar、José Manuel Alonso、Gregor J. Macdonald、Daniel Oehlrich、Hilde Lavreysen、Abdelah Ahnaou、Wilhelmus Drinkenburg、Claire Mackie、Stefan Pype、David Gallacher、Andrés A. Trabanco

  DOI：10.1021/jm500496m

  日期：2014.8.14

  We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.