N-(4-methylcyclohexyl)-1,8-naphthyridin-2(1H)-on-3-carboxamide | 1160012-27-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(4-methylcyclohexyl)-1,8-naphthyridin-2(1H)-on-3-carboxamide
• 英文别名: N-(4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide；N-(4-methylcyclohexyl)-2-oxo-1H-1,8-naphthyridine-3-carboxamide
• CAS: 1160012-27-0
• 化学式: C₁₆H₁₉N₃O₂
• 分子量: 285.346
• InChiKey: OXLSZQTXORXHBY-UHFFFAOYSA-N

物化性质

• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  71.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(4-methylcyclohexyl)-1,8-naphthyridin-2(1H)-on-3-carboxamide 在 caesium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 5-(3-(4-methylcyclohexylcarbamoyl)-2-oxo-1,8-naphthyridin-1(2H)-yl)pentyl methanesulfonate
  参考文献：
  名称：

  CB2-Selective Cannabinoid Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of 1,8-Naphthyridin-2(1H)-one-3-carboxamides

  摘要：

  We have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (chi 1 g+ -> trans) transition

  DOI：

  10.1021/jm500807e
• 作为产物：
  描述：

  2-氨基-3-吡啶甲醛 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 36.0h， 生成 N-(4-methylcyclohexyl)-1,8-naphthyridin-2(1H)-on-3-carboxamide
  参考文献：
  名称：

  Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells

  摘要：

  多项研究表明，大麻素能降低肿瘤生长、抑制血管生成和减少癌细胞迁移。由于这些分子具有良好的耐受性，因此研究与大麻素受体（CBRs）结合的新合成化合物的潜在益处是很有意义的。在这项研究中，我们描述了 2-氧代-1,8-萘啶-3-甲酰胺衍生物 LV50 的合成和生物效应，这是一种具有高 CB2 受体（CB2R）亲和力的新化合物。通过胰蓝和 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑（MTT）的评估，我们发现它能降低 Jurkat 白血病细胞的活力，但主要是诱导细胞凋亡。我们通过碘化丙啶染色和 Hoechst 33258 观察到低二倍体峰的增加以及核形态的变化。Annexin V 染色、核酶聚（ADP-核糖）聚合酶（PARP）裂解和 caspases 激活的显著增加证实了这些数据。此外，为了排除 LV50 非特异性地引发所有正常白细胞死亡的可能性，我们在正常外周血淋巴细胞上测试了这种新化合物，排除了一般细胞毒性的可能性。为了确定 CB2R 在 LV50 的抗增殖和促凋亡作用中的参与情况，我们用一种特异性 CB2R 拮抗剂对细胞进行了预处理，结果显示了相反的结果。因此，我们认为这种新化合物作为选择性 CB2R 激动剂，在抑制细胞存活和促进细胞凋亡活性之间存在联系。

  DOI：

  10.3390/ijms19071958

文献信息

• Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain
  作者：Rodrigo Teodoro、Daniel Gündel、Winnie Deuther-Conrad、Lea Ueberham、Magali Toussaint、Guy Bormans、Peter Brust、Rareş-Petru Moldovan

  DOI：10.3390/ijms22158051

  日期：——

  development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is

  2 型大麻素受体 (CB2R) 是神经退行性疾病和癌症的有吸引力的治疗靶点。针对开发正电子发射断层扫描 (PET) 放射性示踪剂以在 CB2R 定制治疗期间监测受体密度和/或占用率，我们在此描述了顺式-[ 18 F]1-(4-氟丁基-N -( (1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8- naphthyridine -3-carboxamide ([ 18 F] LU14 ) 从相应的甲磺酸盐前体开始。第一次生物学评估表明[ 18楼] LU14 是一种高度亲和的 CB2R 放射性配体，注射后 30 分钟在大脑中具有 >80% 的完整示踪剂 它在一个完善的 CB2R 过表达大鼠模型中通过 PET 的进一步评估证明了它能够选择性地对大脑中的 CB2R 成像，并且具有作为示踪剂以进一步研究 CB2R 表达的疾病相关变化。
• Rational Design, Synthesis, and Pharmacological Properties of New 1,8-Naphthyridin-2(1<i>H</i>)-on-3-Carboxamide Derivatives as Highly Selective Cannabinoid-2 Receptor Agonists
  作者：Clementina Manera、Giuseppe Saccomanni、Barbara Adinolfi、Veronica Benetti、Alessia Ligresti、Maria Grazia Cascio、Tiziano Tuccinardi、Valentina Lucchesi、Adriano Martinelli、Paola Nieri、Emanuela Masini、Vincenzo Di Marzo、Pier Luigi Ferrarini

  DOI：10.1021/jm801563d

  日期：2009.6.25

  concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB2 agonists.

  CB 2受体激活可用于治疗诸如慢性疼痛和免疫原性肿瘤等缺乏精神活性的疾病。根据我们已经报道的1,8-萘啶-4（1 H）-3-羧酰胺衍生物，设计，合成了新的1,8-萘啶-2（1 H）-3-羧酰胺衍生物。并测试了它们对人CB 1和CB 2大麻素受体的亲和力。一些报道的化合物显示一个亚纳摩尔CB 2亲和力与CB 1 / CB 2选择性比率大于200（化合物6，12，顺式-12，13，以及顺式- 13）。进一步的研究表明，化合物12呈现出在1和3位上结合的苄基和羧基-4-甲基环己基酰胺取代基，它对人体免疫性嗜碱性粒细胞的活化具有CB 2介导的抑制作用。在人类T细胞白血病品系Jurkat上，相同的衍生物诱导了细胞存活率的浓度依赖性降低。获得的结果表明1,8-萘啶-2（1 H）-on-3-羧酰胺代表一种非常适合开发新的有前途的CB 2激动剂的新支架。
• Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells
  作者：Antonella Capozzi、Vincenzo Mattei、Stefano Martellucci、Valeria Manganelli、Giuseppe Saccomanni、Tina Garofalo、Maurizio Sorice、Clementina Manera、Roberta Misasi

  DOI：10.3390/ijms19071958

  日期：——

  Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.

  多项研究表明，大麻素能降低肿瘤生长、抑制血管生成和减少癌细胞迁移。由于这些分子具有良好的耐受性，因此研究与大麻素受体（CBRs）结合的新合成化合物的潜在益处是很有意义的。在这项研究中，我们描述了 2-氧代-1,8-萘啶-3-甲酰胺衍生物 LV50 的合成和生物效应，这是一种具有高 CB2 受体（CB2R）亲和力的新化合物。通过胰蓝和 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑（MTT）的评估，我们发现它能降低 Jurkat 白血病细胞的活力，但主要是诱导细胞凋亡。我们通过碘化丙啶染色和 Hoechst 33258 观察到低二倍体峰的增加以及核形态的变化。Annexin V 染色、核酶聚（ADP-核糖）聚合酶（PARP）裂解和 caspases 激活的显著增加证实了这些数据。此外，为了排除 LV50 非特异性地引发所有正常白细胞死亡的可能性，我们在正常外周血淋巴细胞上测试了这种新化合物，排除了一般细胞毒性的可能性。为了确定 CB2R 在 LV50 的抗增殖和促凋亡作用中的参与情况，我们用一种特异性 CB2R 拮抗剂对细胞进行了预处理，结果显示了相反的结果。因此，我们认为这种新化合物作为选择性 CB2R 激动剂，在抑制细胞存活和促进细胞凋亡活性之间存在联系。
• Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells
  作者：Francesca Gado、Rebecca Ferrisi、Sarah Di Somma、Fabiana Napolitano、Kawthar A. Mohamed、Lesley A. Stevenson、Simona Rapposelli、Giuseppe Saccomanni、Giuseppe Portella、Roger G. Pertwee、Robert B. Laprairie、Anna Maria Malfitano、Clementina Manera

  DOI：10.3390/molecules27093019

  日期：——

  obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their

  1,8-萘啶-3-甲酰胺结构先前被认为是一种有前景的支架，可从中获得具有抗癌和抗炎活性的 CB2R 激动剂。这项工作描述了对 CB2R 具有高亲和力和选择性的新型 1,8-naphthyridin-2(1 H )-one-3-carboxamides 的合成和功能表征。新化合物能够在药理学上调节 cAMP 反应，而不调节 CB2R 依赖性 β-arrestin2 募集。还评估了这些结构对 SH-SY5Y 和 SK-N-BE 细胞的抗癌活性。他们能够通过 CB2R 介导的机制以微摩尔效力降低两种神经母细胞瘤癌细胞系的细胞活力（SH-SY5Y 细胞中FG158a的 IC 50 = 11.8 μM， FG160a = 13.2 μM）。最后，在 SH-SY5Y 细胞中，新合成的化合物之一FG158a能够通过 CB2R 介导的作用调节 ERK1/2 的表达，从而表明该信号通路可能参与其潜在的抗癌作用。
• Design, synthesis and preliminary evaluation of 18F-labelled 1,8-naphthyridin- and quinolin-2-one-3-carboxamide derivatives for PET imaging of CB2 cannabinoid receptor
  作者：Giuseppe Saccomanni、Giancarlo Pascali、Sara Del Carlo、Daniele Panetta、Mariarosaria De Simone、Simone Bertini、Silvia Burchielli、Maria Digiacomo、Marco Macchia、Clementina Manera、Piero A. Salvadori

  DOI：10.1016/j.bmcl.2015.04.055

  日期：2015.6

  In the present work, we report the synthesis of new aryliodonium salts used as precursors of single-stage nucleophilic F-18 radiofluorination. The corresponding unlabelled fluorinated derivatives showed to be CB2 cannabinoid receptor specific ligands, with K-i values in the low nanomolar range and high CB2/CB1 selectivity. The radiolabelled compound [F-18] CB91, was successfully formulated for in vivo administration, and its preliminary biodistribution was assessed with microPET/CT. This tracer presented a reasonable in vivo stability and a preferential extraction in the tissues that constitutionally express CB2 cannabinoid receptor. The results obtained indicate [18F] CB91 as a possible candidate marker of CB2 cannabinoid receptor distribution. This study would open the way to further validation of this tracer for assessing pathologies for which the expression of this receptor is modified. (C) 2015 Published by Elsevier Ltd.