8-(cyclopropylmethoxy)-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline | 1257138-52-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 8-(cyclopropylmethoxy)-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline
• CAS: 1257138-52-5
• 化学式: C₂₂H₂₁FN₄O
• 分子量: 376.433
• InChiKey: GEVPWAZNJXIORL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  52.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-fluoro-8-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline 在 三溴化硼 、 caesium carbonate 作用下， 以 1,1-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 8-(cyclopropylmethoxy)-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline
  参考文献：
  名称：

  Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors

  摘要：

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

  DOI：

  10.1021/jm2009138

文献信息

• [EN] SUBSTITUTED IMIDAZO[1,5-a]QUINOXALINES AS INHIBITORS OF PHOSPHODIESTERASE 10<br/>[FR] IMIDAZO[1,5-A]QUINOXALINES SUBSTITUÉES EN TANT QU'INHIBITEURS DE LA PHOSPHODIESTÉRASE 10
  申请人：WYETH CORP

  公开号：WO2010138833A1

  公开（公告）日：2010-12-02

  The invention relates to imidazo[1,5-a]quinoxaline derivatives which are inhibitors of phosphodiesterase 10 (PDE10) useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.

  该发明涉及imidazo[1,5-a]quinoxaline衍生物，它们是磷酸二酯酶10（PDE10）的抑制剂，可用于治疗中枢神经系统疾病，如精神病，也可用于治疗肥胖症、2型糖尿病、代谢综合征、葡萄糖不耐受和疼痛等疾病。
• Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors
  作者：Michael S. Malamas、Yike Ni、James Erdei、Hans Stange、Rudolf Schindler、Hans-Joachim Lankau、Christian Grunwald、Kristi Yi Fan、Kevin Parris、Barbara Langen、Ute Egerland、Thorsten Hage、Karen L. Marquis、Steve Grauer、Julie Brennan、Rachel Navarra、Radka Graf、Boyd L. Harrison、Albert Robichaud、Thomas Kronbach、Menelas N. Pangalos、Norbert Hoefgen、Nicholas J. Brandon

  DOI：10.1021/jm2009138

  日期：2011.11.10

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.