(S)-N-((3-fluoro-4-(trifluoromethyl)phenyl)(2-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (S)-N-((3-fluoro-4-(trifluoromethyl)phenyl)(2-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide
• 英文别名: N-[(S)-[3-fluoro-4-(trifluoromethyl)phenyl]-[2-(trifluoromethyl)phenyl]methyl]quinoline-7-carboxamide
• 化学式: C₂₅H₁₅F₇N₂O
• 分子量: 492.396
• InChiKey: JOMVQQIEZJEVHN-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  42
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  邻溴三氟甲苯 在 盐酸 、 magnesium 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， 反应 10.58h， 生成 (S)-N-((3-fluoro-4-(trifluoromethyl)phenyl)(2-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide
  参考文献：
  名称：

  Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine

  摘要：

  Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a non-selective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

  DOI：

  10.1021/acs.jmedchem.8b00518

文献信息

• Discovery of TRPM8 Antagonist (<i>S</i>)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine
  作者：Daniel B. Horne、Kaustav Biswas、James Brown、Michael D. Bartberger、Jeffrey Clarine、Carl D. Davis、Vijay K. Gore、Scott Harried、Michelle Horner、Matthew R. Kaller、Sonya G. Lehto、Qingyian Liu、Vu V. Ma、Holger Monenschein、Thomas T. Nguyen、Chester C. Yuan、Beth D. Youngblood、Maosheng Zhang、Wenge Zhong、Jennifer R. Allen、Jian Jeffrey Chen、Narender R. Gavva

  DOI：10.1021/acs.jmedchem.8b00518

  日期：2018.9.27

  Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a non-selective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.