N-(3-hydroxy-4-chlorophenyl)-2-picolinamide | 1454840-93-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-hydroxy-4-chlorophenyl)-2-picolinamide
• 英文别名: N-(4-chloro-3-hydroxyphenyl)-2-picolinamide；N-(4-chloro-3-hydroxyphenyl)picolinamide；ML128-OH；nor-ML128；N-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxamide
• CAS: 1454840-93-7
• 化学式: C₁₂H₉ClN₂O₂
• 分子量: 248.669
• InChiKey: PTPKXTGNWYXBOH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  62.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  fluoromethyl-d2 4-methylbenzenesulfonate 、 N-(3-hydroxy-4-chlorophenyl)-2-picolinamide 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 72.0h， 以80.4%的产率得到N-(4-chloro-3-(fluoromethoxy-d2)phenyl)-2-picolinamide
  参考文献：
  名称：

  Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability

  摘要：

  In recent years, mGlu(4) has received great attention and research effort because of the potential benefits of mGlu(4) activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu(4) have been developed. To better understand the role of mGlu(4) in healthy and disease conditions, we are interested in developing an mGlu(4) selective radioligand for in vivo studies. Thus, we had synthesized and studied [C-11]2 as a PET tracer for mGlu(4), which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu(4) ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu(4). The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu(4) ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.07.031
• 作为产物：
  描述：

  2-吡啶甲酸 、 2-氯-5-氨基苯酚 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 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 为溶剂， 以27.8%的产率得到N-(3-hydroxy-4-chlorophenyl)-2-picolinamide
  参考文献：
  名称：

  Radiosynthesis of N-(4-chloro-3-[11C]methoxyphenyl)-2-picolinamide ([11C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4)

  摘要：

  N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu(4) positive allosteric modulator (PAM), which is potent and centrally penetrating. 3 is also the first mGlu(4) PAM to show efficacy in a preclinical Parkinson disease model upon systemic dosing. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers a possibility to investigate mGlu(4) expression in vivo under physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([C-11]3) as a PET radiotracer for mGlu(4), and characterized its biological properties in Sprague Dawley rats. [C-11]3 was synthesized from N-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [C-11]CH3I. Total synthesis time was 38 +/- 2.2 min (n = 7) from the end of bombardment to the formulation. The radioligand [C-11] 3 was obtained in 27.7 +/- 5.3% (n = 5) decay corrected radiochemical yield based on the radioactivity of [C-11]CO2. The radiochemical purity of [C-11]3 was >99%. Specific activity was 188.7 +/- 88.8 GBq/mol (n = 4) at the end of synthesis (EOS).PET images were conducted in 20 normal male Sprague Dawley rats including 11 control studies, 6 studies blocking with an mGlu(4) modulator (4) to investigate specificity and 3 studies blocking with an mGlu(5) modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [C-11]3 (peak activity between 1-3 min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu(4) modulator 4 showed 22-28% decrease of [C-11]3 accumulation while studies of selectivity showed only minor decrease supporting good selectivity over mGlu(5). Biodistribution studies and blood analyses support fast metabolism. Altogether this is the first PET imaging ligand for mGlu(4), in which the labeled ML128 was used for imaging its in vivo distribution and pharmacokinetics in brain. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.07.046

文献信息

• [EN] MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR 4<br/>[FR] MODULATEURS DU RÉCEPTEUR DU GLUTAMATE MÉTABOTROPIQUE 4
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2020146515A1

  公开（公告）日：2020-07-16

  The present application provides picolinamide compounds that can be used as allosteric positron emission tomography ("PET") imaging probes. Methods of using these compounds for treating a neurodegenerative disease are also provided.

  本申请提供了可以用作变构位置发射断层扫描（PET）成像探针的吡啶甲酰胺化合物。同时还提供了利用这些化合物治疗神经退行性疾病的方法。
• Synthesis and Characterization of Fluorine-18-Labeled <i>N</i>-(4-Chloro-3-((fluoromethyl-<i>d</i>₂)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain
  作者：Junfeng Wang、Xiying Qu、Timothy M. Shoup、Gengyang Yuan、Sepideh Afshar、Chuzhi Pan、Aijun Zhu、Ji-Kyung Choi、Hye Jin Kang、Pekka Poutiainen、Georges El Fakhri、Zhaoda Zhang、Anna-Liisa Brownell

  DOI：10.1021/acs.jmedchem.0c00201

  日期：2020.3.26

  characterized [18F]-N-(4-chloro-3-((fluoromethyl-d2)thio)phenyl)-picolinamide ([18F]15) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [18F]15 displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was

  我们合成并表征了[18F]-N-(4-氯-3-((氟甲基-d2)硫代)苯基)-吡啶甲酰胺([18F]15)作为正电子发射断层扫描(PET)成像的潜在配体大脑中的 mGluR4。放射性配体 [18F]15 显示出中枢神经系统药物样特性，包括 mGluR4 亲和力、有效的 mGluR4 PAM 活性、针对其他 mGluR 的选择性以及足够的代谢稳定性。放射合成分两步进行。 [18F]15 的放射化学产率为 11.6 ± 2.9%（n = 7，衰减校正），纯度为 99%，摩尔活度为 84.1 ± 11.8 GBq/μmol。离体生物分布研究表明 [18F]15 在所有研究组织中可逆结合，包括脑、肝、心、肺和肾。雄性 Sprague Dawley 大鼠的 PET 成像研究表明，[18F]15 在已知表达 mGluR4 的大脑区域积聚。用未标记的 mGluR4 PAM 化合物 13（甲硫基类似物）和
• Radiosynthesis and Evaluation of an ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Metabotropic Glutamate Receptor Subtype 4 (mGlu₄)
  作者：Kun-Eek Kil、Pekka Poutiainen、Zhaoda Zhang、Aijun Zhu、Ji-Kyung Choi、Kimmo Jokivarsi、Anna-Liisa Brownell

  DOI：10.1021/jm501245b

  日期：2014.11.13

  Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with F-18. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [F-18]3 at the end of synthesis (EOS) was 233.5 +/- 177.8 GBq/mu mol (n = 4). The radiochemical yield of [F-18]3 was 16.4 +/- 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [F-18]3 is the first F-18-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.
• MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR 4
  申请人：The General Hospital Corporation

  公开号：US20220118117A1

  公开（公告）日：2022-04-21

  The present application provides picolinamide compounds that can be used as allosteric positron emission tomography (“PET”) imaging probes. Methods of using these compounds for treating a neurodegenerative disease are also provided.
• Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability
  作者：Zhaoda Zhang、Kun-Eek Kil、Pekka Poutiainen、Ji-Kyung Choi、Hye-Jin Kang、Xi-Ping Huang、Bryan L. Roth、Anna-Liisa Brownell

  DOI：10.1016/j.bmcl.2015.07.031

  日期：2015.9

  In recent years, mGlu(4) has received great attention and research effort because of the potential benefits of mGlu(4) activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu(4) have been developed. To better understand the role of mGlu(4) in healthy and disease conditions, we are interested in developing an mGlu(4) selective radioligand for in vivo studies. Thus, we had synthesized and studied [C-11]2 as a PET tracer for mGlu(4), which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu(4) ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu(4). The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu(4) ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability. (C) 2015 Elsevier Ltd. All rights reserved.