N-benzyl-3-methyl-N-phenylpyridazine-4-carboxamide | 1071783-04-4

• 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-methyl-N-phenylpyridazine-4-carboxamide
• 英文别名: 3-methyl-pyridazine-4-carboxylic acid benzyl-phenyl-amide
• CAS: 1071783-04-4
• 化学式: C₁₉H₁₇N₃O
• 分子量: 303.363
• InChiKey: WUJQRODSBNDMTF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  46.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-乙酰基-4-戊酸乙酯 在 臭氧 、 一水合肼 、 lithium hydroxide 、 苏丹红 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 8.0h， 生成 N-benzyl-3-methyl-N-phenylpyridazine-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

• PYRIDAZINE-, PYRIDINE- AND PYRANE-DERIVATIVES AS GPBAR1 AGONISTS
  申请人：Arista Luca

  公开号：US20100048579A1

  公开（公告）日：2010-02-25

  A compound of formula (I) wherein the substituents have various meanings, optionally in salt and/or solvate form, and their use as pharmaceuticals.

  一种化合物，其化学式为（I），其中取代基具有不同的含义，可选为盐和/或溶剂化合物形式，并且可以用作药物。
• PYRIDAZINE-, PYRIDINE- AND PYRANE-DERIVATIVES AS GPBAR1 AGONISIS
  申请人：Novartis AG

  公开号：EP2146970A1

  公开（公告）日：2010-01-27
• [EN] PYRIDAZINE-, PYRIDINE- AND PYRANE-DERIVATIVES AS GPBAR1 AGONISIS<br/>[FR] DÉRIVÉS DE PYRIDAZINE, DE PYRIDINE ET DE PYRANE EN TANT QU'AGONISTES DE GPBARL
  申请人：NOVARTIS AG

  公开号：WO2008125627A1

  公开（公告）日：2008-10-23

  [EN] A compound of formula (I) wherein the substituents have various meanings, optionally in salt and/or solvate form, and their use as pharmaceuticals.
  [FR] L'invention porte sur un composé de formule (I) dans laquelle les substituants ont diverses significations, facultativement sous forme de sel et/ou de solvate, et sur leur utilisation comme produits pharmaceutiques.
• 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.