3-Tert-butyl-5-[3-(2,6-dimethoxypyridin-3-yl)-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one | 1435972-30-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-Tert-butyl-5-[3-(2,6-dimethoxypyridin-3-yl)-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one
• 英文别名: 3-tert-butyl-5-[3-(2,6-dimethoxypyridin-3-yl)-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one
• CAS: 1435972-30-7
• 化学式: C₂₆H₃₁N₅O₅
• 分子量: 493.563
• InChiKey: AMXBWRBOUBSUAT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-(3-溴-4-甲氧基苯基)-2-氯乙酮 在 盐酸 、 四(三苯基膦)钯 、 tin(II) chloride dihdyrate 、 sodium carbonate 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 3-Tert-butyl-5-[3-(2,6-dimethoxypyridin-3-yl)-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one
  参考文献：
  名称：

  Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: Optimization studies and demonstration of in vivo efficacy

  摘要：

  Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F = 78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3 h after a single, 10 mg/kg, subcutaneous dose. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.082

文献信息

• Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: Optimization studies and demonstration of in vivo efficacy
  作者：Mark S. Plummer、Joseph Cornicelli、Howard Roark、Donald J. Skalitzky、Charles J. Stankovic、Susan Bove、Jayvardhan Pandit、Annise Goodman、James Hicks、Aurash Shahripour、David Beidler、Xiao Kang Lu、Brian Sanchez、Christopher Whitehead、Ron Sarver、Timothy Braden、Richard Gowan、Xi Qiang Shen、Katherine Welch、Adam Ogden、Nalini Sadagopan、Heidi Baum、Howard Miller、Craig Banotai、Cindy Spessard、Sandra Lightle

  DOI：10.1016/j.bmcl.2013.03.082

  日期：2013.6

  Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F = 78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3 h after a single, 10 mg/kg, subcutaneous dose. (C) 2013 Elsevier Ltd. All rights reserved.