(2S)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-[2-[[4-(trifluoromethoxy)phenyl]methoxy]-3-pyridyl]-2-thienyl]acetamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-[2-[[4-(trifluoromethoxy)phenyl]methoxy]-3-pyridyl]-2-thienyl]acetamide
• 英文别名: (2S)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-[2-[[4-(trifluoromethoxy)phenyl]methoxy]pyridin-3-yl]thiophen-2-yl]acetamide
• 化学式: C₂₉H₂₆F₃N₃O₆S₂
• 分子量: 633.669
• InChiKey: GXGDUSSGELSHSV-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  160
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  苯乙硫醚 在 吡啶 、 盐酸 、 aluminum (III) chloride 、 palladium 10% on activated carbon 、 盐酸羟胺 、 氢气 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 间氯过氧苯甲酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 异丙醇 为溶剂， 反应 47.58h， 生成 (2R)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-[2-[[4-(trifluoromethoxy)phenyl]methoxy]-3-pyridyl]-2-thienyl]acetamide 、 (2S)-2-acetamido-2-(4-ethylsulfonylphenyl)-N-[4-[2-[[4-(trifluoromethoxy)phenyl]methoxy]-3-pyridyl]-2-thienyl]acetamide
  参考文献：
  名称：

  Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

  摘要：

  Retinoic acid receptor related orphan receptor gamma t (ROR gamma t), has been identified as the master regulator of T(H)17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T(H)17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

  DOI：

  10.1021/acs.jmedchem.8b00783

文献信息

• Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design
  作者：Frank Narjes、Yafeng Xue、Stefan von Berg、Jesper Malmberg、Antonio Llinas、Roine I. Olsson、Johan Jirholt、Hanna Grindebacke、Agnes Leffler、Nafizal Hossain、Matti Lepistö、Linda Thunberg、Hanna Leek、Anna Aagaard、Jane McPheat、Eva L. Hansson、Elisabeth Bäck、Stefan Tångefjord、Rongfeng Chen、Yao Xiong、Ge Hongbin、Thomas G. Hansson

  DOI：10.1021/acs.jmedchem.8b00783

  日期：2018.9.13

  Retinoic acid receptor related orphan receptor gamma t (ROR gamma t), has been identified as the master regulator of T(H)17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T(H)17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.