2,6-dimethyl-3,5-dicarbomethoxy-4-(3-cyanophenyl)-1,4-dihydropyridine | 32947-20-9

• 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: 2,6-dimethyl-3,5-dicarbomethoxy-4-(3-cyanophenyl)-1,4-dihydropyridine
• 英文别名: Dimethyl 4-(3-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
• CAS: 32947-20-9
• 化学式: C₁₈H₁₈N₂O₄
• 分子量: 326.352
• InChiKey: HZUHJHPPIRVTJR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  88.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,6-dimethyl-3,5-dicarbomethoxy-4-(3-cyanophenyl)-1,4-dihydropyridine 在 硝酸 作用下， 反应 1.0h， 以61%的产率得到4-(3-Cyano-phenyl)-2,6-dimethyl-pyridine-3,5-dicarboxylic acid dimethyl ester
  参考文献：
  名称：

  人肝微粒体对4-芳基和4-烷基取代的2,6-二甲基-3,5-双（烷氧基羰基）-1,4-二氢吡啶的氧化作用和涉及细胞色素P-450形式的免疫化学证据。

  摘要：

  4-取代的2,6-二甲基-3,5-双（烷氧基羰基）-1,4-二氢吡啶很重要，因为它们作为钙通道阻滞剂。检查了人肝微粒体对14个4-芳基和四个4-烷基取代的衍生物的混合功能氧化。所有4-芳基化合物的酶促氧化的主要产物是含有4-芳基的吡啶衍生物。相反，4-烷基化合物形成吡啶衍生物，其中在4-位存在氢原子并且烷基丢失；这些化合物还使细胞色素P-450失活，并在酶促氧化后导致硝苯地平氧化酶活性丧失。所有这些反应均受到针对纯化的人肝硝苯地平氧化酶细胞色素P-450（P-450NF）的抗体的抑制，表明该酶在这些化合物的氧化中起主要作用。4-烷基化合物的氧化不仅导致P-450NF的损失，而且还导致细胞色素P-450同工酶催化其他反应（非那西丁O-去乙基化和己糖3'-羟基化）的催化活性降低。结果表明，P-450NF（或密切相关的酶形式）负责人肝微粒体中这些硝苯地平相关化合物的氧化，并且代谢高度依赖于4-取

  DOI：

  10.1021/jm00159a007
• 作为产物：
  描述：

  3-氰基苯甲醛 、 乙酰乙酸甲酯 在 ammonium acetate 作用下， 以 甲醇 为溶剂， 反应 24.0h， 生成 2,6-dimethyl-3,5-dicarbomethoxy-4-(3-cyanophenyl)-1,4-dihydropyridine
  参考文献：
  名称：

  发现新的对称和不对称含腈 1,4-二氢吡啶衍生物作为双激酶和 P-糖蛋白抑制剂：合成、体外测定和计算机研究

  摘要：

  摘要 设计、合成和评估了两个新系列的对称 ( 1a-h)和不对称 ( 2a-l) 1,4-DHP 衍生物作为抗癌剂。通过国家癌症研究所“NCI”对目标化合物进行的体外抗癌筛查显示，类似物1g、2e和2l具有抗增殖作用，平均生长抑制百分比“GI%”分别为 41、28 和 64。检查了化合物1g、2e和2l的逆转阿霉素 (DOX) 作用，并说明了具有更好的 IC 50 细胞毒活性= 1.12、3.64 和 3.57 µM，分别。通过估计它们的表皮生长因子受体 (EGFR)、人表皮生长因子受体 2 (HER-2) 和布鲁顿酪氨酸激酶 (BTK) 来检查最活跃的抗癌类似物1g、2e和2l的推定作用机制) 抑制活性。此外，还评估了目标化合物对六种不同病原体的抗菌活性，然后确定了最活跃的类似物的最小抑制浓度“MIC”值。实现了分子对接研究，以了解所选抑制剂与不同生物靶标之间的相互作用模式。

  DOI：

  10.1080/14756366.2022.2120478

文献信息

• Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
  申请人：——

  公开号：US20020119989A1

  公开（公告）日：2002-08-29

  The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction. Moreover, the invention relates to a method of screening a chemical compound for inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca).

  本发明涉及具有对中间电导性Ca2+激活钾通道（IK Ca）具有抑制活性的化合物，以及利用这种化合物治疗或缓解与免疫功能紊乱相关的疾病或症状。此外，本发明涉及一种筛选化合物对中间电导性Ca2+激活钾通道（IK Ca）具有抑制活性的方法。
• Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects
  作者：Meng-Xing Huang、Yi-Jing Tian、Chuan Han、Run-Duo Liu、Xi Xie、Yijun Yuan、Yi-Yi Yang、Zhe Li、Jianwen Chen、Hai-Bin Luo、Yinuo Wu

  DOI：10.1021/acs.jmedchem.2c00458

  日期：2022.6.23

  previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited

  我们之前的研究表明，磷酸二酯酶 1 (PDE1) 可以作为对抗特发性肺纤维化的潜在靶点。据报道，尼莫地平是一种常用于改善高血压的钙拮抗剂，对 PDE1 有抑制作用。在此，一系列尼莫地平类似物被发现是经过结构修饰后的新型选择性和有效的 PDE1 抑制剂。化合物2g对 PDE1C 表现出优异的抑制活性 (IC 50 = 10 nM)，对除 PDE4 之外的其他 PDE 具有高选择性，并且具有较弱的钙通道拮抗活性。复方2g给药在博莱霉素诱导的肺纤维化大鼠模型中表现出显着的治疗作用，并阻止了TGF-β1诱导的肌成纤维细胞分化。发现PDE1B和PDE1C的表达增加并集中在纤维化病灶。化合物2g增加了肺纤维化大鼠肺中 3',5'-环磷酸腺苷 (cAMP) 和 3',5'-环磷酸鸟苷 (cGMP) 的水平, 支持了抗纤维化作用的事实。2g均通过cAMP和cGMP的调节。
• Long acting formulation
  申请人：SYNTEX (U.S.A.) INC.

  公开号：EP0301133A2

  公开（公告）日：1989-02-01

  A long acting sustained release pharmaceutical composition for dihydropyridine calcium channel blockers wherein the calcium channel blocker and a pH-dependent binder are intimately admixed in essentially spherically shaped non-rugose particles of up to 1.2 mm in diameter.

  一种用于二氢吡啶类钙通道阻滞剂的长效缓释药物组合物，其中钙通道阻滞剂和一种 pH 值依赖性粘合剂紧密混合在直径不超过 1.2 毫米的球形非rugose 颗粒中。
• Oxidation of dihydropyridine calcium channel blockers and analogs by human liver cytochrome P-450 IIIA4
  作者：F. Peter Guengerich、William R. Brian、Masahiko Iwasaki、Marie Agnes Sari、Catharina Baeaernhielm、Peder Berntsson

  DOI：10.1021/jm00110a012

  日期：1991.6

  A series of 21 different 4-substituted 2,6-dimethyl-3-(alkoxycarbonyl)-1,4-dihydropyridines was considered with regard to oxidation to pyridine derivatives by human liver microsomal cytochrome P-450 (P-450). Antibodies raised against P-450 IIIA4 inhibited the microsomal oxidation of nifedipine and felodipine to the same extent, as did cimetidine and the mechanism-based inactivator gestodene. Gestodene was approximately 10(3) times more effective an inhibitor than cimetidine, on a molar basis. When rates of oxidation of the 1,4-dihydropyridines were compared to each other in different human liver microsomal preparations, all were highly correlated with each other with the exceptions of a derivative devoid of a substituent at the 4-position and an N1-CH3 derivative. A P-4.50 IIIA4 cDNA clone was expressed in yeast and the partially purified protein was used in reconstituted systems containing NADPH-cytochrome P-450 reductase and cytochrome b5. This system catalyzed the oxidation of all of the 1,4-dihydropyridines except the two for which poor correlation was seen in the liver microsomes. Principal component analysis supported the view that most of these reactions were catalyzed by the same enzyme in the yeast P-450 IIIA4 preparation and in the different human liver microsomal preparations, or by a closely related enzyme showing nearly identical properties of catalytic specificity and regulation. The results indicate that the enzyme P-450 IIIA4 is probably the major human catalyst involved in the formal dehydrogenation of most but not all 1,4-dihydropyridine drugs.
• 1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure-activity relationship approach
  作者：Robert A. Coburn、Mark Wierzba、Mark J. Suto、Alan J. Solo、A. M. Triggle、David J. Triggle

  DOI：10.1021/jm00119a009

  日期：1988.11

  The effect of 46 1,4-dihydropyridine-type calcium channel antagonists on the tonic contractile response of longitudinal muscle strips of guinea pig ileum was determined. 2,6-Dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine (13) and 13 ortho-, 15 meta-, and seven para-monosubstituted and 10 polysubstituted aromatic derivatives of 13 were studied. The pharmacological activities of the monosubstituted derivatives were best correlated by eq 10, log 1/C = 0.68 pi + 2.50 sigma m -0.47Lmeta -3.40B1para + 11.31, which had a correlation coefficient of 0.89. The full data set was best correlated by eq 11, log 1/C = 0.62 pi + 1.96 sigma m -0.44Lmeta -3.26B1para -1.51Lmeta' + 14.23, which had a correlation coefficient of 0.90. Equations of similar form but involving an ortho steric term were found to correlate the radioligand binding data for this class of compounds.