1-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
• 英文别名: 1-(2-Fluoro-4-pyrrolidin-1-ylphenyl)-5-methoxy-3-(2-phenylpyrazol-3-yl)pyridazin-4-one；1-(2-fluoro-4-pyrrolidin-1-ylphenyl)-5-methoxy-3-(2-phenylpyrazol-3-yl)pyridazin-4-one
• 化学式: C₂₄H₂₂FN₅O₂
• 分子量: 431.469
• InChiKey: JMJCLBKZPINABC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  63
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  四氢吡咯 、 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以49%的产率得到1-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
  参考文献：
  名称：

  Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor

  摘要：

  Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl) phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.10.002

文献信息

• Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor
  作者：Masato Yoshikawa、Haruhi Kamisaki、Jun Kunitomo、Hideyuki Oki、Hironori Kokubo、Akihiro Suzuki、Tomomi Ikemoto、Kosuke Nakashima、Naomi Kamiguchi、Akina Harada、Haruhide Kimura、Takahiko Taniguchi

  DOI：10.1016/j.bmc.2015.10.002

  日期：2015.11

  Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl) phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. (C) 2015 Elsevier Ltd. All rights reserved.