3-(7-methoxy-1-methyl-β-carbolin-9-yl)propionic acid methyl ester

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 3-(7-methoxy-1-methyl-β-carbolin-9-yl)propionic acid methyl ester
• 英文别名: Methyl 3-(7-methoxy-1-methylpyrido[3,4-b]indol-9-yl)propanoate；methyl 3-(7-methoxy-1-methylpyrido[3,4-b]indol-9-yl)propanoate
• 化学式: C₁₇H₁₈N₂O₃
• 分子量: 298.342
• InChiKey: QLMKOBFAGMGYOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  53.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(7-methoxy-1-methyl-β-carbolin-9-yl)propionic acid methyl ester 在 草酰氯 、 lithium hydroxide monohydrate 、 氨 、 水 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 13.0h， 生成 3-(7-methoxy-1-methyl-β-carbolin-9-yl)propionamide
  参考文献：
  名称：

  基于结构的设计和合成在激酶与单胺氧化酶抑制作用下具有不同选择性的Harmine衍生物。

  摘要：

  双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）是一种新兴的生物学靶标，涉及多种治疗领域，例如神经系统疾病（尤其是唐氏综合症），代谢和肿瘤学。Harmine是一种在激酶中选择性抑制DYRK1A的天然产物，可以用作工具化合物，以更好地了解DYRK1A抑制作用引起的生物学过程。另一方面，harmine还是单胺氧化酶A（MAO-A）的有效抑制剂。使用基于结构的设计，我们合成了对这两种酶具有可调选择性的harmine类似物集合。在7位的修饰通常会降低对DYRK1A的亲和力，而在9位的取代对MAO-A的抑制作用相似，但仍保持DYRK1A的抑制作用。

  DOI：

  10.1002/cmdc.201600539
• 作为产物：
  描述：

  3-溴丙酸甲酯 、 肉叶云香碱 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 以81%的产率得到3-(7-methoxy-1-methyl-β-carbolin-9-yl)propionic acid methyl ester
  参考文献：
  名称：

  Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor

  摘要：

  Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.

  DOI：

  10.1021/acs.jmedchem.9b01379

文献信息

• KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
  申请人：Icahn School of Medicine at Mount Sinai

  公开号：US20210094950A1

  公开（公告）日：2021-04-01

  Described herein are compounds having the following structure: formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof. Also disclosed are compositions containing the compounds, methods of inhibiting activity of DYRK1 A in a cell, methods of increasing cell proliferation in a population of pancreatic beta cells, methods of treating a subject for a condition associated with insufficient insulin secretion, and methods of treating a subject for a neurological disorder.