trans-(E)-N-[4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-phenyl-2-propenamide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: trans-(E)-N-[4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-phenyl-2-propenamide
• 化学式: C₂₇H₃₁N₃O
• 分子量: 413.563
• InChiKey: ATLSVLPVZPFHBU-ONRAHDBNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.69
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  56.13
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  TERT-BUTYL TRANS-4-(2-OXOETHYL)CYCLOHEXYLCARBAMATE 在 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 32.0h， 生成 trans-(E)-N-[4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-phenyl-2-propenamide
  参考文献：
  名称：

  Design and Synthesis of trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2- yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011):  A Potent and Selective Dopamine D₃ Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat

  摘要：

  A selective dopamine D-3 receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3,4-tetrahydroisoquinolines, exemplified by 13, was identified with high D-3 affinity and selectivity against the D-2 receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl Linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano -1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (24, SB-277011). This compound is a potent and selective dopamine D-3 receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D-3 receptor in the CNS.

  DOI：

  10.1021/jm000090i

文献信息

• Design and Synthesis of <i>trans</i>-<i>N</i>-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2- yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011):  A Potent and Selective Dopamine D₃ Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat
  作者：Geoffrey Stemp、Tracey Ashmeade、Clive L. Branch、Michael S. Hadley、A. Jacqueline Hunter、Christopher N. Johnson、David J. Nash、Kevin M. Thewlis、Antonio K. K. Vong、Nigel E. Austin、Phillip Jeffrey、Kim Y. Avenell、Izzy Boyfield、Jim J. Hagan、Derek N. Middlemiss、Charlie Reavill、Graham J. Riley、Carole Routledge、Martyn Wood

  DOI：10.1021/jm000090i

  日期：2000.5.1

  A selective dopamine D-3 receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3,4-tetrahydroisoquinolines, exemplified by 13, was identified with high D-3 affinity and selectivity against the D-2 receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl Linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano -1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (24, SB-277011). This compound is a potent and selective dopamine D-3 receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D-3 receptor in the CNS.