6-(7-methoxy-1-methyl-β-carbolin-9-yl)hexanoic acid hydrochloride

• 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: 6-(7-methoxy-1-methyl-β-carbolin-9-yl)hexanoic acid hydrochloride
• 英文别名: 6-(7-Methoxy-1-methylpyrido[3,4-b]indol-9-yl)hexanoic acid;hydrochloride；6-(7-methoxy-1-methylpyrido[3,4-b]indol-9-yl)hexanoic acid;hydrochloride
• 化学式: C₁₉H₂₂N₂O₃*ClH
• 分子量: 362.856
• InChiKey: AUXYNFZPGIVEMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.57
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  64.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6-(7-methoxy-1-methyl-β-carbolin-9-yl)hexanoic acid t-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 以100%的产率得到6-(7-methoxy-1-methyl-β-carbolin-9-yl)hexanoic acid hydrochloride
  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.
• 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
  作者：Kunal Kumar、Peng Wang、Jessica Wilson、Viktor Zlatanic、Cecilia Berrouet、Susmita Khamrui、Cody Secor、Ethan A. Swartz、Michael Lazarus、Roberto Sanchez、Andrew F. Stewart、Adolfo Garcia-Ocana、Robert J. DeVita

  DOI：10.1021/acs.jmedchem.9b01379

  日期：2020.3.26

  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.