(R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline | 1589601-95-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
• 英文别名: (1R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline
• CAS: 1589601-95-5
• 化学式: C₁₆H₁₃F₄N
• 分子量: 295.28
• InChiKey: XFRUKPLOROZCIF-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-1,1,1-三氟丙-2-胺 、 (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 、 N,N'-羰基二咪唑 以 四氢呋喃 、 二氯甲烷 为溶剂， 以61.2%的产率得到(R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
  参考文献：
  名称：

  Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

  摘要：

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.

  DOI：

  10.1021/jm401955h
• 作为产物：
  描述：

  3-fluoro-N-phenethyl-4-(trifluoromethyl)-benzamide 在 sodium tetrahydroborate 、 四磷十氧化物 、 三氯氧磷 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 38.0h， 生成 (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

  摘要：

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.

  DOI：

  10.1021/jm401955h

文献信息

• Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists
  作者：Daniel B. Horne、Nuria A. Tamayo、Michael D. Bartberger、Yunxin Bo、Jeffrey Clarine、Carl D. Davis、Vijay K. Gore、Matthew R. Kaller、Sonya G. Lehto、Vu V. Ma、Nobuko Nishimura、Thomas T. Nguyen、Phi Tang、Weiya Wang、Beth D. Youngblood、Maosheng Zhang、Narender R. Gavva、Holger Monenschein、Mark H. Norman

  DOI：10.1021/jm401955h

  日期：2014.4.10

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.