3-(2-(cyclohexylamino)pyridin-4-yl)-4-(naphthalen-2-yl)-1-(pyridin-4-ylmethyl)-1H-1,2,4-triazol-5(4H)-one | 1268247-68-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(2-(cyclohexylamino)pyridin-4-yl)-4-(naphthalen-2-yl)-1-(pyridin-4-ylmethyl)-1H-1,2,4-triazol-5(4H)-one
• 英文别名: 5-[2-(cyclohexylamino)pyridin-4-yl]-4-naphthalen-2-yl-2-(pyridin-4-ylmethyl)-1,2,4-triazol-3-one
• CAS: 1268247-68-2
• 化学式: C₂₉H₂₈N₆O
• 分子量: 476.581
• InChiKey: IOZQORJWOUBHKH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  73.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-(2-bromopyridin-4-yl)-4-(naphthalen-2-yl)-2-(pyridin-4-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 、 环己胺 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 生成 3-(2-(cyclohexylamino)pyridin-4-yl)-4-(naphthalen-2-yl)-1-(pyridin-4-ylmethyl)-1H-1,2,4-triazol-5(4H)-one
  参考文献：
  名称：

  Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration

  摘要：

  In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.

  DOI：

  10.1016/j.bmcl.2010.11.010

文献信息

• Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration
  作者：Gary D. Probst、Simeon Bowers、Jennifer M. Sealy、Anh P. Truong、Roy K. Hom、Robert A. Galemmo、Andrei W. Konradi、Hing L. Sham、David A. Quincy、Hu Pan、Nanhua Yao、May Lin、Gergley Tóth、Dean R. Artis、Wes Zmolek、Karina Wong、Ann Qin、Colin Lorentzen、David F. Nakamura、Kevin P. Quinn、John-Michael Sauer、Kyle Powell、Lany Ruslim、Sarah Wright、David Chereau、Zhao Ren、John P. Anderson、Frédérique Bard、Ted A. Yednock、Irene Griswold-Prenner

  DOI：10.1016/j.bmcl.2010.11.010

  日期：2011.1

  In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.