(R)-N-(4-cyanophenylethyl)-1-(6-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide hydrochloride | 1595144-54-9

• 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-(6-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide hydrochloride
• CAS: 1595144-54-9
• 化学式: C₂₄H₂₈F₃N₇O*ClH
• 分子量: 523.989
• InChiKey: MGXVUWIUSGWCIK-FSRHSHDFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.77
• 重原子数：
  36.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  97.18
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  3-氧杂环丁酮 、 (R)-N-(4-cyanophenylethyl)-1-(6-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide hydrochloride 在 溶剂黄146 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以25%的产率得到(R)-N-(4-cyanophenylethyl)-1-(6-(4-(oxetan-3-yl)piperazin-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
• 作为产物：
  描述：

  在 N,N-二异丙基乙胺 作用下， 以 异丙醇 为溶剂， 反应 1.67h， 生成 (R)-N-(4-cyanophenylethyl)-1-(6-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide hydrochloride
  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