1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone | 1227174-96-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone
• 英文别名: 1-[4-[2-[4-(1H-benzimidazole-2-carbonyl)phenoxy]pyridin-3-yl]piperidin-1-yl]ethanone
• CAS: 1227174-96-0
• 化学式: C₂₆H₂₄N₄O₃
• 分子量: 440.502
• InChiKey: AKOCZUMLNYFJPF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  88.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-羟基-1-哌啶甲酸苄酯 在 咪唑 、 三甲基氯硅烷 、 palladium 10% on activated carbon 、 氢气 、 碘 、 caesium carbonate 、 溶剂黄146 、 1,2-二溴乙烷 、 三苯基膦 、 锌 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 N,N-二甲基乙酰胺 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 反应 38.83h， 生成 1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone
  参考文献：
  名称：

  Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)

  摘要：

  We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.

  DOI：

  10.1021/jm500713j

文献信息

• PYRIDINE AND PYRIMIDINE DERIVATIVES AS PHOSPHODIESTERASE 10 INHIBITORS
  申请人：Allen Jennifer R.

  公开号：US20100125062A1

  公开（公告）日：2010-05-20

  Pyridine and pyrimidine 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.

  吡啶和嘧啶化合物，以及含有它们的组合物，以及制备这些化合物的方法。本文还提供了治疗通过抑制PDE10可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症等。
• Pyridine and pyrimidine derivatives as phosphodiesterase 10 inhibitors
  申请人：Amgen Inc.

  公开号：EP2364306A1

  公开（公告）日：2011-09-14
• US8318718B2
  申请人：——

  公开号：US8318718B2

  公开（公告）日：2012-11-27
• US8759532B2
  申请人：——

  公开号：US8759532B2

  公开（公告）日：2014-06-24
• [EN] PYRIDINE AND PYRIMIDINE DERIVATIVES AS PHOSPHODIESTERASE 10 INHIBITORS<br/>[FR] DERIVES DE PYRIDINE ET DE PYRIMIDINE COMME INHIBITEURS DE PHOSPHODIESTERASE 10
  申请人：AMGEN INC

  公开号：WO2010057126A1

  公开（公告）日：2010-05-20

  Pyridine and pyrimidine 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.