7-((pyridin-3-ylmethyl)amino)-3-(quinolin-8-ylmethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 7-((pyridin-3-ylmethyl)amino)-3-(quinolin-8-ylmethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
• 英文别名: 7-(Pyridin-3-ylmethylamino)-3-(quinolin-8-ylmethyl)-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-4-one；7-(pyridin-3-ylmethylamino)-3-(quinolin-8-ylmethyl)-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-4-one
• 化学式: C₂₆H₂₃N₅OS
• 分子量: 453.568
• InChiKey: MQFKBKSSWPIHMP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  98.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  8-溴甲基喹啉 在 三乙酰氧基硼氢化钠 、 caesium carbonate 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 7-((pyridin-3-ylmethyl)amino)-3-(quinolin-8-ylmethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket

  摘要：

  Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.

  DOI：

  10.1021/acs.jmedchem.6b01690

文献信息

• Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket
  作者：Sandeep Sundriyal、Sébastien Moniot、Zimam Mahmud、Shang Yao、Paolo Di Fruscia、Christopher R. Reynolds、David T. Dexter、Michael J. E. Sternberg、Eric W.-F. Lam、Clemens Steegborn、Matthew J. Fuchter

  DOI：10.1021/acs.jmedchem.6b01690

  日期：2017.3.9

  Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.