2,3-bis(hydroxymethyl)-6-cyclopentyloxy-7-methoxy-1-<2-<1(2H)-phthalazinon-4-(3-pyridyl)-2-yl>-4-pyridyl>-naphthalene

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2,3-bis(hydroxymethyl)-6-cyclopentyloxy-7-methoxy-1-<2-<1(2H)-phthalazinon-4-(3-pyridyl)-2-yl>-4-pyridyl>-naphthalene
• 英文别名: 2-[4-[6-Cyclopentyloxy-2,3-bis(hydroxymethyl)-7-methoxynaphthalen-1-yl]pyridin-2-yl]-4-pyridin-3-ylphthalazin-1-one
• 化学式: C₃₆H₃₂N₄O₅
• 分子量: 600.674
• InChiKey: DKLXINMEXJFCET-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  45
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-氯吡啶-4-甲醛 在 palladium on activated charcoal 正丁基锂 、 三氟化硼乙醚 、 氢气 、 sodium hydride 、 一水合肼 、 溶剂黄146 、 红铝 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇 、 甲苯 、 乙腈 、 xylene 为溶剂， -70.0~120.0 ℃ 、310.26 kPa 条件下， 反应 33.5h， 生成 2,3-bis(hydroxymethyl)-6-cyclopentyloxy-7-methoxy-1-<2-<1(2H)-phthalazinon-4-(3-pyridyl)-2-yl>-4-pyridyl>-naphthalene
  参考文献：
  名称：

  Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents:  Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

  摘要：

  The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585 . HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at; a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0.85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the K-i value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).

  DOI：

  10.1021/jm980314l

文献信息

• Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents:  Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives
  作者：Tatsuzo Ukita、Masakatsu Sugahara、Yoshihiro Terakawa、Tooru Kuroda、Kazuteru Wada、Aya Nakata、Yasushi Ohmachi、Hideo Kikkawa、Katsuo Ikezawa、Kazuaki Naito

  DOI：10.1021/jm980314l

  日期：1999.3.1

  The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585 . HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at; a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0.85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the K-i value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).