4'-(((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-4-fluoro-[1,1'-biphenyl]-2-carbonitrile | 1374671-66-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4'-(((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-4-fluoro-[1,1'-biphenyl]-2-carbonitrile
• 英文别名: 4'-((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-ylthio)methyl)-4-fluorobiphenyl-2-carbonitrile；2-[4-[[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1,3,4-oxadiazol-2-yl]sulfanylmethyl]phenyl]-5-fluorobenzonitrile
• CAS: 1374671-66-5
• 化学式: C₂₄H₁₆FN₃O₃S
• 分子量: 445.474
• InChiKey: WYYSOGMUPDEQEM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4'-(((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-4-fluoro-[1,1'-biphenyl]-2-carbonitrile 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 48.0h， 以79%的产率得到4'-((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl-sulfinyl)methyl)-4-fluorobiphenyl-2-carbonitrile
  参考文献：
  名称：

  Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

  摘要：

  The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML) may require alpha-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3 alpha selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3 alpha/beta with the highest GSK-3 alpha selectivity reported to dtae. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3 alpha targeting in AML cell lines was achieved with compound 27, resulting in a strong differrentiation phenotype and colony formation impairment, confirming the potential of GSK-3 alpha inhibition in AML therapy.

  DOI：

  10.1021/acs.jmedchem.5b01200
• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二噁烷-6-羧酸 在 一水合肼 、 三乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 66.0h， 生成 4'-(((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-4-fluoro-[1,1'-biphenyl]-2-carbonitrile
  参考文献：
  名称：

  Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3α

  摘要：

  The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-3 alpha and GSK-3 beta to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3 alpha-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3 alpha inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-3 alpha selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.

  DOI：

  10.1021/jm300309a

文献信息

• VALPROIC ACID COMPOUNDS AND WNT AGONISTS FOR TREATING EAR DISORDERS
  申请人：Frequency Therapeutics, Inc.

  公开号：US20220133740A1

  公开（公告）日：2022-05-05

  The present invention provides methods for treating diseases and disorders of the ear with valproic acid compounds and Wnt agonists. The present invention further provides kits for the same.
• [DE] DERIVATE VON 2-BENZYLSULFANYL[1,3,4]-OXADIAZOL UND DEREN MEDIZINISCHE VERWENDUNG<br/>[EN] 2-BENZYLSULFANYL[1,3,4]-OXADIAZOLE DERIVATIVES, AND MEDICAL USE THEREOF<br/>[FR] DÉRIVÉS DE 2-BENZYLSULFANYL[1,3,4]OXADIAZOLE ET UTILISATION DESDITS DÉRIVÉS EN MÉDECINE
  申请人：UNIV DARMSTADT TECH

  公开号：WO2013007663A1

  公开（公告）日：2013-01-17

  Die vorliegende Erfindung betrifft Verbindungen, die als selektive Liganden der Glykogen Synthase Kinase 3 (GSK-3) wirken und für die Behandlung von GSK-3-vermittelten Erkrankungen verwendet werden können. Die erfindungsgemäßen Verbindungen wirken als Inhibitoren der Glykogen Synthase Kinase 3 (GSK-3).