cis-6-(3,4-dimethoxybenzoyl)cyclohex-3-enecarboxylic acid

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: cis-6-(3,4-dimethoxybenzoyl)cyclohex-3-enecarboxylic acid
• 英文别名: cis-6-(3,4-dimethoxybenzoyl)cyclohex-3-ene-1-carboxylic acid；6-(3,4-dimethoxybenzoyl)cyclohex-3-enecarboxylic acid；(1S,6R)-6-(3,4-dimethoxybenzoyl)cyclohex-3-ene-1-carboxylic acid
• 化学式: C₁₆H₁₈O₅
• 分子量: 290.316
• InChiKey: IVDZZBBOYNNPHS-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  cis-6-(3,4-dimethoxybenzoyl)cyclohex-3-enecarboxylic acid 在 一水合肼 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 生成 (cis)-4-(3,4-Dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  新型选择性磷酸二酯酶（PDE4）抑制剂。4.顺式-四氢和顺式六氢邻苯二氮酮的拆分，绝对构型和PDE4抑制活性。

  摘要：

  最近，我们报道了4-儿茶酚取代的顺-（+/-）-4a，5,6,7,8,8a-六-和顺-（+/-）-4a，5,8,8a-四氢-2H-酞嗪-1-酮显示出对磷酸二酯酶（PDE4）活性的有效抑制作用，而相应的反式外消旋混合物仅表现出弱至中等的活性。为了确定各个顺式对映异构体的绝对构型和PDE4抑制活性，已合成了几种旋光性邻苯二氮酮。用作起始原料的各种γ-酮酸的对映异构体通过形成非对映异构体盐以经典方式拆分，然后以对映选择性的方式将其分别转化为旋光性酞嗪酮。顺式六氢酞嗪酮（+）-12的（+）-对映体的绝对构型通过X射线晶体学测定。发现在4a和8a位置的碳原子分别具有S-和R-构型。在本系列的六氢和四氢邻苯二氮酮中，观察到了对PDE4抑制的立体选择性。邻苯二氮酮的顺-（+）-对映体显示高抑制活性，而它们的（-）-对映体仅显示弱至中等活性。对于顺式（-）-类似物，所有顺式（+）-邻苯二氮酮都可能具有（4

  DOI：

  10.1021/jm0110338
• 作为产物：
  描述：

  邻苯二甲醚 、 cis-1,2,3,6-tetrahydrophthalic anhydride 在 aluminum (III) chloride 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 cis-6-(3,4-dimethoxybenzoyl)cyclohex-3-enecarboxylic acid
  参考文献：
  名称：

  合成和评估苯基吡啶哒嗪酮NPD-001作为有效的锥虫TbrPDEB1磷酸二酯酶抑制剂和体外锥虫杀虫剂的类似物

  摘要：

  锥虫磷酸二酯酶B1和B2（TbrPDEB1和TbrPDEB2）在布鲁氏锥虫的生命周期中起着重要作用，布鲁氏锥虫是人类非洲锥虫病（HAT）的致病性寄生虫，也被称为非洲昏睡病。击倒这两种酶会导致细胞周期停滞，并且对寄生虫具有致命性。最近，我们报道了phenylpyridazinone，NPD-001，具有低纳摩尔IC 50个在两个TbrPDEB1值（IC 50：4 1nM）和TbrPDEB2（IC 50：3 nM）的（。传染病杂志 2012，206（229）。在这项研究中，我们现在报告一系列作为TbrPDEB1抑制剂的苯基哒嗪酮类似物的第一个结构活性关系。还显示了选择的化合物是抗寄生虫的。重要的是，观察到TbrPDEB1 IC 50和EC 50与整个寄生虫之间具有良好的相关性。对TbrPDEB1和人PDE上所选化合物的SAR的初步分析显示出很大的差异，这显示出获得寄生虫选择性PDE抑制剂的潜力

  DOI：

  10.1016/j.bmc.2016.02.032

文献信息

• 3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity
  作者：Yang Zheng、Joachim Müller、Stefan Kunz、Marco Siderius、Louis Maes、Guy Caljon、Norbert Müller、Andrew Hemphill、Geert Jan Sterk、Rob Leurs

  DOI：10.1016/j.ijpddr.2022.05.004

  日期：2022.8

  As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2-b]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia, with a nitroimidazole scaffold to generate

  由于对新型抗感染药物的持续需求，本研究旨在将两种作用模式融合到新型 3-硝基咪唑并[1,2- b ]哒嗪支架中，以提高抗寄生虫功效。为此，我们将磷酸二酯酶抑制剂的已知结构元素（最近提出的针对布氏锥虫和贾第鞭毛虫的靶标）与硝基咪唑支架结合以产生亚硝化应激。这些化合物在体外针对一组原生动物寄生虫进行了评估，即兰氏贾第鞭毛虫、布氏锥虫、克氏锥虫、婴儿利什曼原虫和恶性疟原虫以及对 MRC-5 细胞的细胞毒性。有趣的是，获得了针对G. lamblia的选择性亚纳摩尔活性，并且通过测试具有和不具有硝基的几种类似物，表明硝基的存在而非 PDE 抑制是低 IC 50值的原因这些新颖的化合物。3-硝基咪唑并[1,2- b ]哒嗪系列的关键化合物具有良好的类药物特性（低分子量、cLogP (1.2–4.1) 和低极性表面积），可被视为进一步研究的有价值的产物。抗贾第虫病药物的探索与开发。
• Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors
  作者：Kohei Kagayama、Tatsuya Morimoto、Seigo Nagata、Fumitaka Katoh、Xin Zhang、Naoki Inoue、Asami Hashino、Kiyoto Kageyama、Jiro Shikaura、Tomoko Niwa

  DOI：10.1016/j.bmc.2009.08.014

  日期：2009.10

  Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure-activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-alpha production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis. (C) 2009 Elsevier Ltd. All rights reserved.
• Novel Selective PDE4 Inhibitors. 1. Synthesis, Structure−Activity Relationships, and Molecular Modeling of 4-(3,4-Dimethoxyphenyl)-2<i>H</i>-phthalazin-1-ones and Analogues
  作者：Margaretha Van der Mey、Armin Hatzelmann、Ivonne J. Van der Laan、Geert J. Sterk、Ulrich Thibaut、Hendrik Timmerman

  DOI：10.1021/jm010837k

  日期：2001.8.1

  A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the eGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.
• Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression
  作者：John R. Cashman、Senait Ghirmai

  DOI：10.1016/j.bmc.2009.08.025

  日期：2009.10

  Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., (R)- and (S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) showed moderately potent serotonin reuptake inhibition (IC(50) values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC(50) values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., K(i) values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression. (C) 2009 Elsevier Ltd. All rights reserved.
• Dual Inhibitors of Phosphodiesterase-4 and Serotonin Reuptake
  作者：John R. Cashman、Troy Voelker、Han-Ting Zhang、James M. O’Donnell

  DOI：10.1021/jm8010993

  日期：2009.3.26

  A new class of multitarget compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI) to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 2-5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine (14) and 2-5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine (15) were both individually linked to the PDE4 inhibitor 4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (19), via a five-carbon chain. The dual PDE4 inhibitor/SSRI 2-5-[3-(5-fluoro-2-methoxyphenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one (21) showed potent and selective serotonin reuptake inhibition (IC50 value of 127 nM). The dual PDE4 inhibitor/SSRI 21 also inhibited PDE4D3 with a K-i value of 2.0 nM. The dual PDE4 inhibitor/SSRI was significantly more effective than the individual SSRI alone or fluoxetine in the forced swim test at standard doses. On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine.