8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1R,4R)-4-methylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1R,4R)-4-methylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one
• 化学式: C₂₅H₃₆N₄O₃S
• 分子量: 472.652
• InChiKey: BFGKWRDOJNKVSF-RQWUDLNCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.83
• 重原子数：
  33.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  90.87
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1R,4R)-4-methylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one 在 20% palladium hydroxide-activated charcoal 、 氢气 作用下， 以 甲醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 18.0h， 生成 1-(3,5-dimethyl-4-(2-((2-((1R,4R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea
  参考文献：
  名称：

  Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

  摘要：

  During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHRl agonist, l-(3,5-dimethyl-4-(2-((2-((lR,4R)-4-methylcyclohexyl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)sulfonyl)ethyl)-phenyl)-l-methylurea (CH5447240, 141). Compound 141 exhibited a potent in vitro hPTHRl agonist effect with EC20 of 3.0 mu M and EC50 of 12 mu M and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 141 showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

  DOI：

  10.1021/acs.jmedchem.8b00182
• 作为产物：
  描述：

  4-氨基-4-氰基-哌啶-1-羧酸叔丁酯 在 盐酸 、 4-二甲氨基吡啶 、 N-甲基二环己基胺 、 双氧水 、 三乙胺 、 sodium hydroxide 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 9.5h， 生成 8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1R,4R)-4-methylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one
  参考文献：
  名称：

  Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

  摘要：

  During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHRl agonist, l-(3,5-dimethyl-4-(2-((2-((lR,4R)-4-methylcyclohexyl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)sulfonyl)ethyl)-phenyl)-l-methylurea (CH5447240, 141). Compound 141 exhibited a potent in vitro hPTHRl agonist effect with EC20 of 3.0 mu M and EC50 of 12 mu M and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 141 showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

  DOI：

  10.1021/acs.jmedchem.8b00182