N-(1-phenylethyl)-5-(benzo[d]imidazol-2(3H)-one)-6H-1,3,4-thiadiazin-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N-(1-phenylethyl)-5-(benzo[d]imidazol-2(3H)-one)-6H-1,3,4-thiadiazin-2-amine
• 英文别名: N-(1-phenylethyl)-5-(benzo[d]imidazol-2(3H)-one-6-yl)-6H-1,3,4-thiadiazin-2-amine；5-[2-(1-Phenylethylimino)-3,6-dihydro-1,3,4-thiadiazin-5-yl]-1,3-dihydrobenzimidazol-2-one；5-[2-(1-phenylethylimino)-3,6-dihydro-1,3,4-thiadiazin-5-yl]-1,3-dihydrobenzimidazol-2-one
• 化学式: C₁₈H₁₇N₅OS
• 分子量: 351.432
• InChiKey: ARZSEJWAYZPZPI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (±)-1-苯乙基硫代异氰酸酯 在 一水合肼 、 溶剂黄146 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 N-(1-phenylethyl)-5-(benzo[d]imidazol-2(3H)-one)-6H-1,3,4-thiadiazin-2-amine
  参考文献：
  名称：

  Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity

  摘要：

  The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic beta-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine I which was found to inhibit DYRK1A with IC50 of 9.41 mu m (K-d = 7.3 mu M). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with significantly improved binding as compared to the initial hit (K-d = 71-185 nM). Compound 3-5 induced human beta-cell proliferation at 5 mu M while showing selectivity for DYRK1A over DYRK1B and DYRK2 at 10 mu M. This newly developed DYRK1A inhibitor scaffold with unique kinase selectivity profiles has potential to be further optimized as novel therapeutics for diabetes. (C) 2018 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2018.08.007

文献信息

• KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
  申请人：ICHAN SCHOOL OF MEDICINE AT MOUNT SINAI

  公开号：US20200306257A1

  公开（公告）日：2020-10-01

  The present invention is directed to kinase inhibitor compounds having the following structure: or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, where R 1 , R 2 , X, n, R 3 , Y, Z, R 4 , R 5 , R 6 , and = are as defined herein. The present invention also relates to compositions containing the kinase inhibitor compounds, methods of inhibiting activity of a kinase 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.
• METHOD OF INCREASING PROLIFERATION OF PANCREATIC BETA CELLS, TREATMENT METHOD, AND COMPOSITION
  申请人：ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

  公开号：US20210032601A1

  公开（公告）日：2021-02-04

  Disclosed herein are methods of increasing cell proliferation in a population of pancreatic beta cells. Also disclosed are methods of treating a subject for a condition associated with insufficient insulin secretion. Also disclosed is a composition comprising a DYRK1 A inhibitor and a GLP1R agonist. The disclosure further describes a method of regenerating pancreatic beta cells in a transplant patient.
• [EN] METHOD OF INCREASING PROLIFERATION OF PANCREATIC BETA CELLS, TREATMENT METHOD, AND COMPOSITION<br/>[FR] PROCÉDÉ D'AUGMENTATION DE LA PROLIFÉRATION DE CELLULES BÊTA PANCRÉATIQUES, PROCÉDÉ DE TRAITEMENT ET COMPOSITION
  申请人：ICAHN SCHOOL MED MOUNT SINAI

  公开号：WO2019136320A1

  公开（公告）日：2019-07-11

  Disclosed herein are methods of increasing cell proliferation in a population of pancreatic beta cells. Also disclosed are methods of treating a subject for a condition associated with insufficient insulin secretion. Also disclosed is a composition comprising a DYRK1 A inhibitor and a GLP1R agonist. The disclosure further describes a method of regenerating pancreatic beta cells in a transplant patient.
• Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity
  作者：Kunal Kumar、Peter Man-Un Ung、Peng Wang、Hui Wang、Hailing Li、Mary K. Andrews、Andrew F. Stewart、Avner Schlessinger、Robert J. DeVita

  DOI：10.1016/j.ejmech.2018.08.007

  日期：2018.9

  The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic beta-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine I which was found to inhibit DYRK1A with IC50 of 9.41 mu m (K-d = 7.3 mu M). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with significantly improved binding as compared to the initial hit (K-d = 71-185 nM). Compound 3-5 induced human beta-cell proliferation at 5 mu M while showing selectivity for DYRK1A over DYRK1B and DYRK2 at 10 mu M. This newly developed DYRK1A inhibitor scaffold with unique kinase selectivity profiles has potential to be further optimized as novel therapeutics for diabetes. (C) 2018 Published by Elsevier Masson SAS.