(R)-N-(2-(6-cyanopyridin-3-yl)ethyl)-1-(6-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide | 1595144-74-3

• 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-(2-(6-cyanopyridin-3-yl)ethyl)-1-(6-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide
• 英文别名: (3R)-N-[2-(6-cyanopyridin-3-yl)ethyl]-1-[6-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-3-carboxamide
• CAS: 1595144-74-3
• 化学式: C₂₄H₂₉F₃N₈O
• 分子量: 502.542
• InChiKey: MKHYOYUIGKEBPI-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2-氯-5-吡啶乙腈 在 racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl 、 盐酸 、 sodium tetrahydroborate 、 palladium(II) trifluoroacetate 、 nickel(II) chloride hexahydrate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 锌 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成 (R)-N-(2-(6-cyanopyridin-3-yl)ethyl)-1-(6-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)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