N,N-di-n-propyl-[2-(6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)]acetamide | 1073119-12-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N,N-di-n-propyl-[2-(6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)]acetamide
• 英文别名: 2-(6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide；CB185；2-[6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide
• CAS: 1073119-12-6
• 化学式: C₂₁H₂₃Cl₂N₃O₂
• 分子量: 420.339
• InChiKey: GKAZPCATGVRFSI-UHFFFAOYSA-N

物化性质

• 熔点：
  212-216 °C
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N,N-di-n-propyl-[2-(6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)]acetamide 在 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl-3,4-dihydroxyphenethylcarbamate
  参考文献：
  名称：

  Novel codrugs with GABAergic activity for dopamine delivery in the brain

  摘要：

  This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period.These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ijpharm.2012.08.023
• 作为产物：
  描述：

  ethyl-2-((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridine-2-yl)phenoxy)carbonylamino)-3-(3,4-dihydroxyphenyl)propanoate 在 甲醇 作用下， 以 aq. phosphate buffer 为溶剂， 生成 N,N-di-n-propyl-[2-(6,8-dichloro-2-(4-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)]acetamide
  参考文献：
  名称：

  Novel codrugs with GABAergic activity for dopamine delivery in the brain

  摘要：

  This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period.These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ijpharm.2012.08.023

文献信息

• 2-Phenyl-imidazo[1,2-<i>a</i>]pyridine Compounds Containing Hydrophilic Groups as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors: Synthesis, Binding Affinity and Electrophysiological Studies
  作者：Nunzio Denora、Valentino Laquintana、Maria Giuseppina Pisu、Riccardo Dore、Luca Murru、Andrea Latrofa、Giuseppe Trapani、Enrico Sanna

  DOI：10.1021/jm8006728

  日期：2008.11.13

  GABA A receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABA A receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion

  合成了一系列咪唑并吡啶乙酰胺，以评估中枢（CBR）和周围苯并二氮杂receptor受体（PBR）的结构变化的影响。这些变化包括在咪唑并吡啶骨架的2位和8位引入极性取代基或可电离的官能团。结果表明，在苯环的对位具有氢键受体和/或供体性质的取代基导致对PBR的高亲和力。在电生理研究中，发现化合物9、12、13和28显着增强了表达α1β2γ2 GABA A受体的非洲爪蟾卵母细胞中GABA诱发的Cl（-）电流。氟马西尼降低化合物9施加的刺激作用的能力支持以下结论：所检测化合物的调节作用涉及CBR。化合物16增加CA1锥体神经元中GABA A受体介导的微型抑制性突触后电流的能力表明其刺激神经甾体的局部合成和分泌的能力。
• Translocator Protein (TSPO) Ligand−Ara-C (Cytarabine) Conjugates as a Strategy To Deliver Antineoplastic Drugs and To Enhance Drug Clinical Potential
  作者：Nunzio Denora、Valentino Laquintana、Adriana Trapani、Angela Lopedota、Andrea Latrofa、James M. Gallo、Giuseppe Trapani

  DOI：10.1021/mp100235w

  日期：2010.12.6

  The aim of this work was to evaluate TSPO ligand-Ara-C conjugation as an approach for the selective delivery of the antineoplastic agent to brain tumors as well as for overcome P-gp resistance induction observed for the majority of cytotoxic agents, enhancing the drug clinical potential. To this end, the novel N-imidazopyridinacetyl-Ara-C conjugates 3a-c, 10 and 15 have been prepared and evaluated for their cytotoxicity against glioma cell lines. In contrast to that observed for 3a-c and 10, the conjugate 15 resulted stable in both phosphate buffer and physiological medium. In all cases, the release of free Ara-C from hydrolyzed conjugates was checked by HPLC and ESI-MS analysis. Conjugates 10 and 15 displayed very high in vitro TSPO affinity and selectivity, and, hence, they may possess potential for targeted brain delivery. Due to the favorable features displayed by the conjugate 15, it was further evaluated on glioma cell lines, expressing high levels of TSPO, in the presence and in the absence of specific nucleoside transport (NT) inhibitors. In contrast to that observed for the free Ara-C, the presence of NT inhibitors did not reduce the cytotoxic activity of 15. Moreover, conjugate 15, as N-4-acyl derivative of Ara-C, should be resistant to inactivation by cytidine deaminase, and it may possess enhanced propensity to target brain tumor cells characterized by a reduced expression of NTs. In addition, this conjugate behaves as a clear P-gp modulator and thereby may be useful to reverse MDR. Transport studies across the MDCKII-MDR1 monolayer indicated that conjugate 15 should overcome the BBB by transcellular pathway. All these features may be useful for enhancing the clinical potential of the nucleoside drug Ara-C.