5-amino-N-cyclopropyl-3-(4-isopropylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide | 1391029-86-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-amino-N-cyclopropyl-3-(4-isopropylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide
• 英文别名: 5-amino-N-cyclopropyl-4-oxo-3-(4-propan-2-ylphenyl)thieno[3,4-d]pyridazine-1-carboxamide
• CAS: 1391029-86-9
• 化学式: C₁₉H₂₀N₄O₂S
• 分子量: 368.459
• InChiKey: MUJBLKVKVLSJQD-UHFFFAOYSA-N

物化性质

• 密度：
  1.48±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  ethyl 5-cyano-1-(4-isopropylphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 lithium hydroxide monohydrate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 、 二甲基亚砜 为溶剂， 反应 20.25h， 生成 5-amino-N-cyclopropyl-3-(4-isopropylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide
  参考文献：
  名称：

  Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties

  摘要：

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.027

文献信息

• Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties
  作者：Carlo Ballatore、Alex Crowe、Francesco Piscitelli、Michael James、Kevin Lou、Gabrielle Rossidivito、Yuemang Yao、John Q. Trojanowski、Virginia M.-Y. Lee、Kurt R. Brunden、Amos B. Smith

  DOI：10.1016/j.bmc.2012.05.027

  日期：2012.7

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.