(R)-N-(4-cyanophenylethyl)-1-(2-trifluoromethyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)piperidine-3-carboxamide | 1595144-49-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-N-(4-cyanophenylethyl)-1-(2-trifluoromethyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)piperidine-3-carboxamide
• 英文别名: (3R)-N-[2-(4-cyanophenyl)ethyl]-1-[6-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-3-carboxamide
• CAS: 1595144-49-2
• 化学式: C₂₅H₃₀F₃N₇O
• 分子量: 501.555
• InChiKey: YMFDSPVIOOOQTH-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  88.4
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-Boc-(R)-3-甲酸哌啶 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 1.75h， 生成 (R)-N-(4-cyanophenylethyl)-1-(2-trifluoromethyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)piperidine-3-carboxamide
  参考文献：
  名称：

  Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy

  摘要：

  Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

  DOI：

  10.1021/jm401731q

文献信息

• COMPOSITIONS AND METHODS FOR THE TREATMENT OF LIVER DISORDERS
  申请人：Viking Therapeutics, Inc.

  公开号：US20220016136A1

  公开（公告）日：2022-01-20

  The present disclosure is directed toward the use of thyroid receptor agonists of pharmaceutically acceptable salts thereof, in combination with a second pharmaceutical agent for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
• Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy
  作者：Dean P. Phillips、Wenqi Gao、Yang Yang、Guobao Zhang、Isabelle K. Lerario、Thomas L. Lau、Jiqing Jiang、Xia Wang、Deborah G. Nguyen、B. Ganesh Bhat、Carol Trotter、Heather Sullivan、Gustav Welzel、Jannine Landry、Yali Chen、Sean B. Joseph、Chun Li、W. Perry Gordon、Wendy Richmond、Kevin Johnson、Angela Bretz、Badry Bursulaya、Shifeng Pan、Peter McNamara、H. Martin Seidel

  DOI：10.1021/jm401731q

  日期：2014.4.24

  Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.