methyl 4-hydroxyisoquinoline-3-carboxylate | 1108146-90-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: methyl 4-hydroxyisoquinoline-3-carboxylate
• 英文别名: Methyl 4-hydroxyisoquinoline-3-carboxylate
• CAS: 1108146-90-2
• 化学式: C₁₁H₉NO₃
• mdl: MFCD28141336
• 分子量: 203.197
• InChiKey: IIIGXUWKEAXZBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  59.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-hydroxyisoquinoline-3-carboxylate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(4-hydroxyisoquinoline-3-carboxamido)morphinan
  参考文献：
  名称：

  Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function

  摘要：

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.07.043
• 作为产物：
  描述：

  1-氯-4-羟基异喹啉-3-羧酸甲酯 在 palladium 10% on activated carbon 、 氢气 、 sodium acetate 作用下， 反应 47.0h， 以66%的产率得到methyl 4-hydroxyisoquinoline-3-carboxylate
  参考文献：
  名称：

  Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function

  摘要：

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.07.043

文献信息

• Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent <i>In Vitro</i> Antileishmanial Activity: Initial SAR and Assessment of <i>In Vivo</i> Activity
  作者：Michael G. Thomas、Manu De Rycker、Richard J. Wall、Daniel Spinks、Ola Epemolu、Sujatha Manthri、Suzanne Norval、Maria Osuna-Cabello、Stephen Patterson、Jennifer Riley、Frederick R. C. Simeons、Laste Stojanovski、John Thomas、Stephen Thompson、Claire Naylor、Jose M. Fiandor、Paul G. Wyatt、Maria Marco、Susan Wyllie、Kevin D. Read、Timothy J. Miles、Ian H. Gilbert

  DOI：10.1021/acs.jmedchem.0c00705

  日期：2020.9.10

  tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.

  内脏利什曼病 (VL) 是一种寄生虫感染，每年导致大约 26 000-65 000 人死亡。可用的治疗方法受到毒性、疗效可变和不合适的剂量选择等问题的阻碍。迫切需要新的治疗方法，这导致了被忽视疾病药物计划(DND i )、葛兰素史克 (GSK) 和邓迪大学之间的合作。8-羟基萘啶被确定为起点，早期化合物在 VL 小鼠模型中表现出较弱的功效，但受到葡萄糖醛酸化的阻碍。解决这个问题的努力导致开发了具有改善体外特征的化合物，但这些化合物在体内耐受性差. 对作用方式 (MoA) 的研究表明，活性是由二价金属阳离子的螯合驱动的，这种机制可能导致耐受性差。这突出了在早期研究表型活性系列的 MoA 和药代动力学的重要性。
• Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist
  作者：Qiu Li、Benqiang Yao、Shiting Zhao、Zhou Lu、Yan Zhang、Qiuping Xiang、Xishan Wu、Haonan Yu、Cheng Zhang、Junhua Li、Xiaoxi Zhuang、Donghai Wu、Yong Li、Yong Xu

  DOI：10.1021/acs.jmedchem.2c00144

  日期：2022.5.26

  The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the “His-Phe switch” to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound 16g, which is a potent TRβ agonist (EC50: 21.0 nM, 85.0% of the maximum

  选择性靶向甲状腺激素受体 β (TRβ) 和 TRβ 突变体的激动剂的设计和开发仍然具有挑战性。在这项研究中，我们首先采用打破“His-Phe 开关”的策略来同时解决两个问题。成功利用基于结构的设计方法获得了化合物16g，它是一种有效的 TRβ 激动剂（EC 50 ：21.0 nM， 1的最大功效的 85.0% ），对 TRβ 的选择性优于对 TRα 的选择性，还可以有效激活 TRβ H435R突变体。然后，我们开发了一种高效的16g合成方法. 我们的一系列共晶结构揭示了克服亚型选择性和拯救 H435R 突变的详细结构机制。16g还表现出优异的脂质代谢、安全性、代谢稳定性和药代动力学特性。总的来说，16g是一种充分表征的选择性和突变敏感的 TRβ 激动剂，用于进一步研究其在治疗血脂异常、非酒精性脂肪性肝炎 (NASH) 和甲状腺激素抵抗 (RTH) 中的作用。
• Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
  作者：Yunyun Yuan、Orgil Elbegdorj、Irina O. Beletskaya、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmcl.2013.07.043

  日期：2013.9

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.
• Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
  作者：Yunyun Yuan、Saheem A. Zaidi、David L. Stevens、Krista L. Scoggins、Philip D. Mosier、Glen E. Kellogg、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmc.2015.02.055

  日期：2015.4

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.