(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone
• 英文别名: 1H-benzimidazol-2-yl-[4-[3-[4-[(2S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]piperidin-1-yl]pyrazin-2-yl]oxyphenyl]methanone
• 化学式: C₂₆H₂₄F₃N₅O₃
• 分子量: 511.503
• InChiKey: ADMPHCQUPDYFKW-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  ethyl 4-(3-chloropyrazin-2-yloxy)benzoate 在 原甲酸三乙酯 、 苯磺酸 作用下， 以 四氢呋喃 、 二甲基亚砜 、 甲苯 为溶剂， 反应 7.0h， 生成 (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone
  参考文献：
  名称：

  Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)

  摘要：

  Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

  DOI：

  10.1021/jm401234w

文献信息

• [EN] PYRAZINE COMPOUNDS AS PHOSPHODIESTERASE 10 INHIBITORS<br/>[FR] COMPOSES DE PYRAZINE COMME INHIBITEURS DE PHOSPHODIESTERASE 10
  申请人：AMGEN INC

  公开号：WO2010057121A1

  公开（公告）日：2010-05-20

  Pyrazine compounds, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

  吡嗪化合物、含有它们的组合物以及制备这些化合物的方法。还提供了通过抑制PDE10治疗可治疗的疾病或病症的方法，例如肥胖、非胰岛素依赖型糖尿病、精神分裂症、双相情感障碍、强迫症等。
• PYRAZINE COMPOUNDS AS PHOSPHODIESTERASE 10 INHIBITORS
  申请人：Allen Jennifer R.

  公开号：US20110160182A1

  公开（公告）日：2011-06-30

  Pyrazine compounds, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

  本发明提供了吡嗪化合物、含有它们的组合物以及制备这些化合物的方法。本发明还提供了治疗通过抑制PDE10可治疗的疾病或疾病的方法，例如肥胖症、非胰岛素依赖性糖尿病、精神分裂症、双相障碍、强迫症等。
• US8053438B2
  申请人：——

  公开号：US8053438B2

  公开（公告）日：2011-11-08
• US8247418B2
  申请人：——

  公开号：US8247418B2

  公开（公告）日：2012-08-21
• US8329700B2
  申请人：——

  公开号：US8329700B2

  公开（公告）日：2012-12-11