trans-2-(2-(1-4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)ethyl-7-cyano-1,2,3,4-tetrahydroisoquinoline | 215790-43-5

• 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: trans-2-(2-(1-4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)ethyl-7-cyano-1,2,3,4-tetrahydroisoquinoline
• 英文别名: tert-butyl (trans-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate
• CAS: 215790-43-5
• 化学式: C₂₃H₃₃N₃O₂
• 分子量: 383.534
• InChiKey: RDLNNBSDNFNODH-CYWCHRQTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.39
• 重原子数：
  28.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  65.36
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  trans-2-(2-(1-4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)ethyl-7-cyano-1,2,3,4-tetrahydroisoquinoline 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 N-(trans-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)acetamide
  参考文献：
  名称：

  A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

  摘要：

  Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4dihydroisoquinolin-2(1H)-yOethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.

  DOI：

  10.1021/jm401318w
• 作为产物：
  描述：

  (2Z)-2-(2-iodophenoxy)but-2-enoic acid 在 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 三乙胺 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 、 甲苯 为溶剂， 生成 trans-2-(2-(1-4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)ethyl-7-cyano-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

  摘要：

  Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4dihydroisoquinolin-2(1H)-yOethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.

  DOI：

  10.1021/jm401318w

文献信息

• Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator <i>N</i>-((<i>trans</i>)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)ethyl)cyclohexyl)-1<i>H</i>-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D₂ Receptor
  作者：Anitha Kopinathan、Christopher Draper-Joyce、Monika Szabo、Arthur Christopoulos、Peter J. Scammells、J. Robert Lane、Ben Capuano

  DOI：10.1021/acs.jmedchem.8b00192

  日期：2019.1.10

  SB269652 (1) is a negative allosteric modulator of the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of “second generation” analogues of 1 whereby subtle modifications to the indole-2-carboxamide motif confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy

  SB269652（1）是多巴胺D 2受体的负变构调节剂。本文中，我们介绍了1的“第二代”类似物的设计，合成和药理学评估，其中对吲哚-2-羧酰胺基序的微妙修饰赋予了功能亲和力（增加了5000倍），协同性（增加了100倍） ），以及调节多巴胺功效的新作用。因此，对该区域1的结构变化允许产生具有不同药理学性质的一组新的类似物。
• Structure–Activity Study of <i>N</i>-((<i>trans</i>)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)ethyl)cyclohexyl)-1<i>H</i>-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D₂ Receptor
  作者：Jeremy Shonberg、Christopher Draper-Joyce、Shailesh N. Mistry、Arthur Christopoulos、Peter J. Scammells、J. Robert Lane、Ben Capuano

  DOI：10.1021/acs.jmedchem.5b00581

  日期：2015.7.9

  We recently demonstrated that 5B269652 (1) engages one protomer of a dopamine D-2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.
• 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.