1-(5-(3-(dimethylamino)phenyl)pyrimidin-2-yl)piperidine-4-carboxamide trifluoroacetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-(5-(3-(dimethylamino)phenyl)pyrimidin-2-yl)piperidine-4-carboxamide trifluoroacetate
• 英文别名: 1-[5-[3-(Dimethylamino)phenyl]pyrimidin-2-yl]piperidine-4-carboxamide;2,2,2-trifluoroacetic acid
• 化学式: C₂HF₃O₂*C₁₈H₂₃N₅O
• 分子量: 439.437
• InChiKey: GOHHVDZNIROIQU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.54
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  哌啶-4-甲酰胺 在 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 2.5h， 生成 1-(5-(3-(dimethylamino)phenyl)pyrimidin-2-yl)piperidine-4-carboxamide trifluoroacetate
  参考文献：
  名称：

  Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators

  摘要：

  Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN, Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models and a starting point for clinical development.

  DOI：

  10.1021/jm200497t

文献信息

• Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators
  作者：Jingbo Xiao、Juan J. Marugan、Wei Zheng、Steve Titus、Noel Southall、Jonathan J. Cherry、Matthew Evans、Elliot J. Androphy、Christopher P. Austin

  DOI：10.1021/jm200497t

  日期：2011.9.22

  Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN, Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models and a starting point for clinical development.