N-benzyl-3,5-dimethyl-N-phenylisoxazole-4-carboxamide | 796100-52-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-benzyl-3,5-dimethyl-N-phenylisoxazole-4-carboxamide
• 英文别名: 3,5-Dimethyl-isoxazole-4-carboxylic acid benzyl-phenyl-amide；N-benzyl-3,5-dimethyl-N-phenyl-1,2-oxazole-4-carboxamide
• CAS: 796100-52-2
• 化学式: C₁₉H₁₈N₂O₂
• mdl: MFCD06372475
• 分子量: 306.364
• InChiKey: XYOWLBDGXLGEGH-UHFFFAOYSA-N

物化性质

• 沸点：
  508.9±50.0 °C(Predicted)
• 密度：
  1.196±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  46.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3,5-二甲基异噁唑-4-羧酸 、 苯甲基苯胺 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 22.0h， 以11%的产率得到N-benzyl-3,5-dimethyl-N-phenylisoxazole-4-carboxamide
  参考文献：
  名称：

  G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype

  摘要：

  GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-alpha and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-alpha and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.

  DOI：

  10.1021/jm501052c

文献信息

• HETEROCYCLIC AMIDES FOR USE AS PHARMACEUTICALS
  申请人：Arista Luca

  公开号：US20100261758A1

  公开（公告）日：2010-10-14

  Compounds of Formula (I) wherein R 1 is aryl, cyclohexyl or heterocyclyl, or (C 1-4 )alkyl substituted by aryl, cyclohexyl or heterocyclyl, R 2 is defined heterocyclyl, R 3 is alkyl, aryl, cyclohexyl or heterocyclyl, or (C 1-4 )alkyl substituted by aryl, cyclohexyl or heterocyclyl, R 4 is H or alkyl, or R 3 and R 4 together with the carbon atom to which they are attached are cycloalkyl fused with aryl, and their use as pharmaceuticals.

  化合物的公式（I），其中R1是芳基，环己基或杂环基，或被芳基，环己基或杂环基取代的（C1-4）烷基，R2是定义的杂环基，R3是烷基，芳基，环己基或杂环基，或被芳基，环己基或杂环基取代的（C1-4）烷基，R4是H或烷基，或R3和R4与它们所连接的碳原子一起是环状烷基与芳基融合，以及它们作为药物的用途。
• G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype
  作者：Klemens Högenauer、Luca Arista、Niko Schmiedeberg、Gudrun Werner、Herbert Jaksche、Rochdi Bouhelal、Deborah G. Nguyen、B. Ganesh Bhat、Layla Raad、Celine Rauld、José M. Carballido

  DOI：10.1021/jm501052c

  日期：2014.12.26

  GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-alpha and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-alpha and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.