methyl 6-((5-cyanopyrazin-2-yl)amino)-4-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)nicotinate | 1137475-93-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: methyl 6-((5-cyanopyrazin-2-yl)amino)-4-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)nicotinate
• 英文别名: methyl 6-(5-cyanopyrazin-2-ylamino)-4-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate
• CAS: 1137475-93-4
• 化学式: C₂₀H₂₃N₇O₂
• 分子量: 393.448
• InChiKey: HUAGSKZSJRBBRA-XMQYKBBCSA-N

物化性质

• 沸点：
  569.8±50.0 °C(predicted)
• 密度：
  1.35±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.31
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  116.06
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  、 2-氨基-5-氰基吡嗪 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 甲苯 为溶剂， 反应 0.5h， 生成 methyl 6-((5-cyanopyrazin-2-yl)amino)-4-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)nicotinate
  参考文献：
  名称：

  Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

  摘要：

  Multiparameter optimization of a series of 5((4-aminopyridin-2-yl)amino)pyrazine-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.5b01938