N-[4-[2-(4-cyanophenoxy)-3-pyridyl]-2-thienyl]-2-(4-ethylsulfonylphenyl)acetamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-[4-[2-(4-cyanophenoxy)-3-pyridyl]-2-thienyl]-2-(4-ethylsulfonylphenyl)acetamide
• 英文别名: N-[4-[2-(4-cyanophenoxy)pyridin-3-yl]thiophen-2-yl]-2-(4-ethylsulfonylphenyl)acetamide
• 化学式: C₂₆H₂₁N₃O₄S₂
• 分子量: 503.602
• InChiKey: CCKGDXBVZQSGGC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  146
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-溴-2-氯吡啶 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium tert-butylate 、 potassium carbonate 、 L-脯氨酸 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.92h， 生成 N-[4-[2-(4-cyanophenoxy)-3-pyridyl]-2-thienyl]-2-(4-ethylsulfonylphenyl)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