5-{[2-fluoro-4-(1H-tetrazol-1-yl)benzyl]oxy}-2-{(2R)-2-methyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}pyrimidine

• 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: 5-{[2-fluoro-4-(1H-tetrazol-1-yl)benzyl]oxy}-2-{(2R)-2-methyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}pyrimidine
• 英文别名: (R)-2-(4-(5-(2-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)pyrimidin-2-yl)-3-methylpiperazin-1-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole；2-[(3R)-4-[5-[[2-fluoro-4-(tetrazol-1-yl)phenyl]methoxy]pyrimidin-2-yl]-3-methylpiperazin-1-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole
• 化学式: C₂₀H₁₈F₄N₁₀O₂
• 分子量: 506.422
• InChiKey: AVUCFLHYBFWMSM-GFCCVEGCSA-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：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  124
• 氢给体数：
  0
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  叔-丁基 4-氨基-2-氟苯甲酸 在 sodium azide 、 硼烷四氢呋喃络合物 、 溶剂黄146 、 甲基磺酰氯 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 81.0h， 生成 5-{[2-fluoro-4-(1H-tetrazol-1-yl)benzyl]oxy}-2-{(2R)-2-methyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]piperazin-1-yl}pyrimidine
  参考文献：
  名称：

  Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

  摘要：

  Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

  DOI：

  10.1021/jm5011012

文献信息

• Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists
  作者：James S. Scott、Suzanne S. Bowker、Katy J. Brocklehurst、Hayley S. Brown、David S. Clarke、Alison Easter、Anne Ertan、Kristin Goldberg、Julian A. Hudson、Stefan Kavanagh、David Laber、Andrew G. Leach、Philip A. MacFaul、Elizabeth A. Martin、Darren McKerrecher、Paul Schofield、Per H. Svensson、Joanne Teague

  DOI：10.1021/jm5011012

  日期：2014.11.13

  Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.