8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1r,4r)-4-ethylcyclohexyl)-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-ethylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one
• 化学式: C₂₆H₃₈N₄O₃S
• 分子量: 486.679
• InChiKey: MYYHMVMVRYIJRS-PHAYBNMGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.22
• 重原子数：
  34.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 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-ethylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one 在 20% palladium hydroxide-activated charcoal 、 氢气 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 21.5h， 生成 1-(4-(2-((2-((1r,4r)-4-ethylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-1-methylurea
  参考文献：
  名称：

  Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

  摘要：

  We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro [4.5] dec-1-en-8-yl)sulfonyl) - ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

  DOI：

  10.1021/acs.jmedchem.9b01743
• 作为产物：
  描述：

  2-((1s,4r)-4-ethylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one bis(2,2,2-trifluoroacetate) 在 盐酸 、 N-甲基二环己基胺 、 三乙胺 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 为溶剂， 反应 2.25h， 生成 8-(((E)-2,6-dimethyl-4-(methylamino)styryl)sulfonyl)-2-((1r,4r)-4-ethylcyclohexyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one
  参考文献：
  名称：

  Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

  摘要：

  We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro [4.5] dec-1-en-8-yl)sulfonyl) - ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

  DOI：

  10.1021/acs.jmedchem.9b01743

文献信息

• Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist
  作者：Yoshikazu Nishimura、Toru Esaki、Yoshiaki Isshiki、Yoshiyuki Furuta、Akemi Mizutani、Tomoya Kotake、Takashi Emura、Yoshiaki Watanabe、Masateru Ohta、Toshito Nakagawa、Kotaro Ogawa、Shinichi Arai、Hiroshi Noda、Hidetomo Kitamura、Masaru Shimizu、Tatsuya Tamura、Haruhiko Sato

  DOI：10.1021/acs.jmedchem.9b01743

  日期：2020.5.28

  We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro [4.5] dec-1-en-8-yl)sulfonyl) - ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.