3-(2-Chlorophenyl)-12-methoxy-7-methyl-5-(trifluoromethyl)-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene | 1340543-38-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(2-Chlorophenyl)-12-methoxy-7-methyl-5-(trifluoromethyl)-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene
• CAS: 1340543-38-5
• 化学式: C₁₈H₁₂ClF₃N₄O
• 分子量: 392.768
• InChiKey: INRSGLNDAUKKFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  52.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  8-methoxy-3-trifluoromethyl-5H-2,5,9,9b-tetraaza-cyclopenta[a]naphthalen-4-one 在 四(三苯基膦)钯 、 potassium carbonate 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 反应 9.0h， 生成 3-(2-Chlorophenyl)-12-methoxy-7-methyl-5-(trifluoromethyl)-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene
  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