3,5-dimethyl-4-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}isoxazole | 1282533-74-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3,5-dimethyl-4-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}isoxazole
• CAS: 1282533-74-7
• 化学式: C₁₃H₂₂N₂O₃S
• 分子量: 286.395
• InChiKey: HSFGRVWTXAIOQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  19.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  63.41
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  3,5-dimethyl-4-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}isoxazole 在 三甲基氯硅烷 、 羟胺 、 乙酸酐 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 丙醇 为溶剂， 生成 N-(4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide
  参考文献：
  名称：

  Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

  摘要：

  A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.028
• 作为产物：
  描述：

  1-(甲基磺酰基)-4-哌啶羧醛 在 palladium on carbon 、 potassium tert-butylate 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 生成 3,5-dimethyl-4-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}isoxazole
  参考文献：
  名称：

  Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

  摘要：

  A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.028

文献信息

• The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis
  作者：Chris De Savi、Andrew Pape、John G. Cumming、Attilla Ting、Peter D. Smith、Jeremy N. Burrows、Mark Mills、Chris Davies、Scott Lamont、David Milne、Calum Cook、Peter Moore、Yvonne Sawyer、Stefan Gerhardt

  DOI：10.1016/j.bmcl.2011.01.036

  日期：2011.3

  Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure–activity

  从筛选以前合成为基质金属蛋白酶-13（胶原酶-3）抑制剂的化合物中鉴定出ADAM-TS4的两个系列N-羟基甲酰胺抑制剂。使用ADAM-TS1作为结构替代物来理解这类化合物的结合模式，导致发现了具有良好DMPK特性的有效且选择性非常强的抑制剂。描述了合成，结构-活性关系以及提高选择性和降低体内代谢清除率的策略。