(R)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidin-5-ol | 1272974-15-8

• 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)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidin-5-ol
• 英文别名: 2-[(2R)-2-methyl-4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]piperazin-1-yl]pyrimidin-5-ol
• CAS: 1272974-15-8
• 化学式: C₁₂H₁₃F₃N₆O₂
• 分子量: 330.269
• InChiKey: YAMBMFDUJNSIFF-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  91.4
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (R)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidin-5-ol 在 potassium carbonate 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 6.0h， 生成 5-({2-fluoro-4-[(S-methylsulfonimidoyl)methyl]benzyl}oxy)-5-({2-fluoro-4-[(S-methylsulfonimidoyl)methyl]benzyl}oxy)-2-{(2R)-2-methyl-4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-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
• 作为产物：
  描述：

  (R)-4-Boc-2-甲基哌嗪 在 盐酸 、 正丁基锂 、 硼酸三异丙酯 、 碳酸氢钠 、 potassium carbonate 、 zinc(II) chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 丁腈 、 正己烷 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 60.33h， 生成 (R)-2-(2-methyl-4-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)pyrimidin-5-ol
  参考文献：
  名称：

  Therapeutic Agents 812

  摘要：

  公式I的化合物或其药用可接受的盐，制备这类化合物的方法，它们作为GPR119调节剂的用途，它们的治疗用途的方法，特别是在肥胖和糖尿病的治疗中，以及含有它们的药物组合物。

  公开号：

  US20110065706A1

文献信息

• Therapeutic Agents 812
  申请人：Birch Alan Martin

  公开号：US20110065706A1

  公开（公告）日：2011-03-17

  A compound of formula I or a pharmaceutically acceptable salt thereof, processes for preparing such compounds, their use as GPR119 modulators, methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and pharmaceutical compositions containing them.

  公式I的化合物或其药用可接受的盐，制备这类化合物的方法，它们作为GPR119调节剂的用途，它们的治疗用途的方法，特别是在肥胖和糖尿病的治疗中，以及含有它们的药物组合物。
• [EN] 4- (PYRIMIDIN-2-YL) -PIPERAZINE AND 4- (PYRIMIDIN-2-YL) -PIPERIDINE DERIVATIVES AS GPR119 MODULATORS<br/>[FR] DERIVES DE 4-(PYRIMIDIN-2-YL)-PIPERAZINE ET DE 4-(PYRIMIDIN-2-YL)-PIPERIDINE UTILISES EN TANT QUE MODULATEURS DU GPR119
  申请人：ASTRAZENECA AB

  公开号：WO2011030139A1

  公开（公告）日：2011-03-17

  A compound of formula (I) or a pharmaceutically acceptable salt thereof, processes for preparing such compounds, their use as GPR119 modulators, methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and pharmaceutical compositions containing them.
• Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation
  作者：James S. Scott、Alan M. Birch、Katy J. Brocklehurst、Anders Broo、Hayley S. Brown、Roger J. Butlin、David S. Clarke、Öjvind Davidsson、Anne Ertan、Kristin Goldberg、Sam D. Groombridge、Julian A. Hudson、David Laber、Andrew G. Leach、Philip A. MacFaul、Darren McKerrecher、Adrian Pickup、Paul Schofield、Per H. Svensson、Pernilla Sörme、Joanne Teague

  DOI：10.1021/jm300310c

  日期：2012.6.14

  G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
• 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.