HJ-I-40 | 1413432-99-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: HJ-I-40
• 英文别名: 8-Ethynyl-N-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide；8-ethynyl-N-methyl-6-pyridin-2-yl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
• CAS: 1413432-99-1
• 化学式: C₂₀H₁₅N₅O
• 分子量: 341.372
• InChiKey: OVDNUOWDLBPRLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  72.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  8-乙炔基-6-吡啶-2-基-4H-咪唑[1,5-a] [1,4]苯并二氮杂-3-羧酸乙酯 、 甲胺 以 乙醇 为溶剂， 反应 24.0h， 以80%的产率得到HJ-I-40
  参考文献：
  名称：

  Search for α3β2/3γ2 subtype selective ligands that are stable on human liver microsomes

  摘要：

  Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABA(A)) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both alpha 2 beta((2/3))gamma 2 (alpha 2BzR) and alpha 3BzR (and/or alpha 2/alpha 3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.10.057

文献信息

• GABAERGIC RECEPTOR SUBTYPE SELECTIVE LIGANDS AND THEIR USES
  申请人：Cook James M.

  公开号：US20120295892A1

  公开（公告）日：2012-11-22

  Described herein are α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands, pharmaceutical compositions, and methods of use of such ligands and compositions in treatment of anxiety disorders, epilepsy and schizophrenia with reduced sedative and ataxic side effects. In embodiments, such as α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands lack ester linkages and may be thus relatively insensitive to hydrolysis by esterases.

  本文描述了α3或α2或α2/α3 GABA能受体亚型选择性配体、药物组合物以及使用这些配体和组合物治疗焦虑症、癫痫和精神分裂症的方法，具有减少镇静和共济失调副作用。在某些实施例中，例如α3或α2或α2/α3 GABA能受体亚型选择性配体不含酯键，因此相对不容易被酯酶水解。
• US9006233B2
  申请人：——

  公开号：US9006233B2

  公开（公告）日：2015-04-14
• US9597342B2
  申请人：——

  公开号：US9597342B2

  公开（公告）日：2017-03-21
• Search for α3β2/3γ2 subtype selective ligands that are stable on human liver microsomes
  作者：Ojas A. Namjoshi、Zhi-jian Wang、Sundari K. Rallapalli、Edward Merle Johnson、Yun-Teng Johnson、Hanna Ng、Joachim Ramerstorfer、Zdravko Varagic、Werner Sieghart、Samarpan Majumder、Bryan L. Roth、James K. Rowlett、James M. Cook

  DOI：10.1016/j.bmc.2012.10.057

  日期：2013.1

  Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABA(A)) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both alpha 2 beta((2/3))gamma 2 (alpha 2BzR) and alpha 3BzR (and/or alpha 2/alpha 3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties. (C) 2012 Elsevier Ltd. All rights reserved.