(R)-4-((2-(2-methylpiperazin-1-yl)pyrimidin-5-yloxy)methyl)nicotinonitrile | 1272973-94-0

• 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)-4-((2-(2-methylpiperazin-1-yl)pyrimidin-5-yloxy)methyl)nicotinonitrile
• 英文别名: 4-[[2-[(2R)-2-methylpiperazin-1-yl]pyrimidin-5-yl]oxymethyl]pyridine-3-carbonitrile
• CAS: 1272973-94-0
• 化学式: C₁₆H₁₈N₆O
• 分子量: 310.359
• InChiKey: YPZUJHLFQXWFNP-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  87
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-4-((2-(2-methylpiperazin-1-yl)pyrimidin-5-yloxy)methyl)nicotinonitrile 、 2,2,2-trifluoroethyl phenyl carbonate 在 三乙胺 作用下， 以 氯仿 为溶剂， 反应 18.0h， 以39%的产率得到2,2,2-trifluoroethyl (3R)-4-{5-[(3-cyanopyridin-4-yl)methoxy]pyrimidin-2-yl}-3-methylpiperazine-1-carboxylate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jm300310c
• 作为产物：
  描述：

  (R)-4-Boc-2-甲基哌嗪 在 盐酸 、 sodium peroxoborate tetrahydrate 、 偶氮二甲酸二异丙酯 、 potassium acetate 、 palladium diacetate 、 potassium carbonate 、 三苯基膦 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 50.5h， 生成 (R)-4-((2-(2-methylpiperazin-1-yl)pyrimidin-5-yloxy)methyl)nicotinonitrile
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jm300310c

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。
• Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists
  作者：James S. Scott、Alan M. Birch、Katy J. Brocklehurst、Hayley S. Brown、Kristin Goldberg、Sam D. Groombridge、Julian A. Hudson、Andrew G. Leach、Philip A. MacFaul、Darren McKerrecher、Ruth Poultney、Paul Schofield、Per H. Svensson

  DOI：10.1039/c2md20130e

  日期：——

  Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.

  改善水溶性是药物发现计划中经常面临的挑战。在本文中，我们描述了通过降低亲脂性和氢键受体调节，在两个GPR119激动剂亚系列中增加了溶解度。利用小分子X射线晶体学研究对固态相互作用的影响。
• 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.