(6,8-Dichloro-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid | 573704-25-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (6,8-Dichloro-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid
• 英文别名: (6,8-Dichloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid；2-(6,8-dichloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid
• CAS: 573704-25-3
• 化学式: C₁₅H₁₀Cl₂N₂O₂
• 分子量: 321.163
• InChiKey: FJSPFFCPOGNEQH-UHFFFAOYSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  54.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (6,8-Dichloro-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 CB50
  参考文献：
  名称：

  2-苯基咪唑并[1,2-α]吡啶衍生物的合成及其对中心和外围苯并二氮杂receptor受体的结合亲和力。针对外围类型的一系列新的高亲和力和选择性配体。

  摘要：

  若干个6-取代或6,8-二取代的2-苯基咪唑并[1,2-α-吡啶-3-羧酸烷基酯5a-h，-乙酸酯5i-s，6a-g和-丙酸酯5t，6h和N，N-二烷基-2-苯基咪唑并[1,2-α吡啶-3-甲酰胺7a-d，-乙酰胺7e-t或-丙酰胺7u是按照新的合成方法制备的，并且它们对两个环的亲和力（CBR ）和外围（PBR）苯并二氮杂receptor受体进行了评估。酯系列化合物对两种受体类型均显示出低亲和力。相反，大多数N，N-二烷基（2-苯基咪唑并[1,2-α吡啶基-3-基]乙酰胺）7e-t对CBR或PBR具有高亲和性和选择性，这取决于C（C 6）-和/或杂环系统上的C（8）。特别是，6-取代的化合物7f-n的IC50值之比（IC50（CBR）/ IC50（PBR））为0.32（7m）至232（7k），而6,8-二取代的化合物7o-t大于PBR的选择性是CBR的1000倍。检查了几种不同的苯二氮卓类

  DOI：

  10.1021/jm970112+
• 作为产物：
  描述：

  (6,8-Dichloro-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid butyl ester 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.0h， 生成 (6,8-Dichloro-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid
  参考文献：
  名称：

  2-苯基咪唑并[1,2-α]吡啶衍生物的合成及其对中心和外围苯并二氮杂receptor受体的结合亲和力。针对外围类型的一系列新的高亲和力和选择性配体。

  摘要：

  若干个6-取代或6,8-二取代的2-苯基咪唑并[1,2-α-吡啶-3-羧酸烷基酯5a-h，-乙酸酯5i-s，6a-g和-丙酸酯5t，6h和N，N-二烷基-2-苯基咪唑并[1,2-α吡啶-3-甲酰胺7a-d，-乙酰胺7e-t或-丙酰胺7u是按照新的合成方法制备的，并且它们对两个环的亲和力（CBR ）和外围（PBR）苯并二氮杂receptor受体进行了评估。酯系列化合物对两种受体类型均显示出低亲和力。相反，大多数N，N-二烷基（2-苯基咪唑并[1,2-α吡啶基-3-基]乙酰胺）7e-t对CBR或PBR具有高亲和性和选择性，这取决于C（C 6）-和/或杂环系统上的C（8）。特别是，6-取代的化合物7f-n的IC50值之比（IC50（CBR）/ IC50（PBR））为0.32（7m）至232（7k），而6,8-二取代的化合物7o-t大于PBR的选择性是CBR的1000倍。检查了几种不同的苯二氮卓类

  DOI：

  10.1021/jm970112+

文献信息

• Novel L-Dopa and Dopamine Prodrugs Containing a 2-Phenyl-imidazopyridine Moiety
  作者：Nunzio Denora、Valentino Laquintana、Angela Lopedota、Mariangela Serra、Laura Dazzi、Giovanni Biggio、Dhananjay Pal、Ashim K. Mitra、Andrea Latrofa、Giuseppe Trapani、Gaetano Liso

  DOI：10.1007/s11095-007-9255-y

  日期：2007.7

  The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds. A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [3H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark’s computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat. Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37°C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [3H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark’s model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P app) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase in cortical dopamine output. Based on these results, it may be concluded that some Dopimid compounds can be proposed as novel L-Dopa and dopamine prodrugs.

  本研究的目的是探讨通过将这些神经递质和L-Dopa乙酯与2-苯基-3-羧甲基-咪唑并吡啶化合物连接，从而增强L-Dopa和多巴胺向大脑输送的可行性，形成所谓的Dopimid化合物。合成了一些Dopimid化合物，并进行了稳定性和对多巴胺能以及苯二氮卓类受体的结合研究。为了评估Dopimid化合物是否为P-gp底物，进行了[3H]利托那韦摄取实验和在趋同MDCKII-MDR1单层上的双向转运研究。通过Clark的计算模型估算了Dopimid化合物的脑穿透特性，并通过调查其在BBMECs单层上的转运进行了评估。在大鼠体内使用脑微透析测量了选定Dopimid化合物腹腔给药后的多巴胺水平。测试的化合物在pH 7.4的缓冲溶液中稳定性良好，但在37°C的稀释大鼠血清中分解速度较快。受体结合研究表明，Dopimid化合物基本上对多巴胺能和苯二氮卓类受体没有亲和力。[3H]利托那韦摄取实验表明，选定的Dopimid化合物，如L-Dopa和氯化多巴胺，并非P-gp底物，这也通过在MDCKII-MDR1单层上的双向转运实验得到了确认。根据Clark的模型，推断出L-Dopa乙酯和多巴胺衍生物具有显著的脑穿透性。涉及BBMECs单层的转运研究表明，这些化合物中的一些应该能够穿过血脑屏障。有趣的是，在这些实验中观察到的表观渗透性（P app）值的排序与计算方法得出的结果相似。在大鼠的脑微透析实验中，腹腔急性给药某些Dopimid化合物会引起皮层多巴胺输出的剂量依赖性增加。基于这些结果，可以得出结论，某些Dopimid化合物可以被提议作为新型的L-Dopa和多巴胺前药。
• 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.
• Structure−Activity Relationships and Effects on Neuroactive Steroid Synthesis in a Series of 2-Phenylimidazo[1,2-<i>a</i>]pyridineacetamide Peripheral Benzodiazepine Receptors Ligands
  作者：Giuseppe Trapani、Valentino Laquintana、Nunzio Denora、Adriana Trapani、Angela Lopedota、Andrea Latrofa、Massimo Franco、Mariangela Serra、Maria Giuseppina Pisu、Ivan Floris、Enrico Sanna、Giovanni Biggio、Gaetano Liso

  DOI：10.1021/jm049610q

  日期：2005.1.1

  A series of 36 imidazopyridineacetamides (2-37) were designed and synthesized to evaluate the effects of structural changes on the amide nitrogen at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include variations in the length and number of the alkyl groups as well as introduction of different aromatic, heteroaromatic, and conformationally constrained groups. The affinities of these compounds for CBRs and PBRs were determined, and the results indicate that bulkiness of the substituents, their branching, and length beyond an optimal value may cause hindrance to the ligand in its interaction with the receptor. The presence of aromatic or conformationally constrained substituents on the carboxamide nitrogen can be conducive to high affinity and selectivity. Furthermore, the ability of a subset of the most active ligands to stimulate synthesis of neuroactive steroids in plasma and brain was evaluated in vivo and in vitro. Compound 3 exhibited very marked effects on the peripheral and central synthesis of neuroactive steroids, while 36 (potent at subnanomolar level) showed a slight ability to affect neuroactive steroid content in the cerebral cortex.
• Alpidem analogues containing a GABA or glycine moiety as new anticonvulsant agents
  作者：Giuseppe Trapani、Andrea Latrofa、Massimo Franco、Antonio Carrieri、Saverio Cellamare、Mariangela Serra、Enrico Sanna、Giovanni Biggio、Gaetano Liso

  DOI：10.1016/s0928-0987(03)00002-2

  日期：2003.3

  Alpidem analogues containing a GABA (1-3) or glycine (4-6) moiety were synthesized and their interaction with the GABA/benzodiazepine receptor complex at central (CBR) and peripheral (PBR) level was evaluated. In particular, their ability to modulate the specific binding of [H-3]-GABA to washed membrane preparations from the rat cerebral cortex, as well as their effects on human recombinant GABA(A) receptors in Xenopus laevis oocytes, were assessed. Results from these in vitro assays showed that the most active compounds were 1 and 4. Intraperitoneal administration of compound 1 at a dose of 150 mg/kg significantly antagonized pentylenetetrazole-induced seizures in rats and the protective effects were evident for 90 min. However, compound 4 failed to interact with strychnine-sensitive Gly-binding sites. Consistent with these binding results, intraperitoneal administration of compound 4 at 150 mg/kg showed no effect against convulsions induced by strychnine, except for a prolonged time of the latency of convulsions. The results obtained suggest that compound 1 possesses interesting anticonvulsant activity and deserves further investigation as a novel lipophilic GABA derivative. (C) 2003 Elsevier Science B.V. All rights reserved.
• Synthesis and Binding Affinity of 2-Phenylimidazo[1,2-<i>a</i>]pyridine Derivatives for both Central and Peripheral Benzodiazepine Receptors. A New Series of High-Affinity and Selective Ligands for the Peripheral Type
  作者：Giuseppe Trapani、Massimo Franco、Laura Ricciardi、Andrea Latrofa、Giuseppe Genchi、Enrico Sanna、Francesca Tuveri、Elisabetta Cagetti、Giovanni Biggio、Gaetano Liso

  DOI：10.1021/jm970112+

  日期：1997.9.1

  prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature

  若干个6-取代或6,8-二取代的2-苯基咪唑并[1,2-α-吡啶-3-羧酸烷基酯5a-h，-乙酸酯5i-s，6a-g和-丙酸酯5t，6h和N，N-二烷基-2-苯基咪唑并[1,2-α吡啶-3-甲酰胺7a-d，-乙酰胺7e-t或-丙酰胺7u是按照新的合成方法制备的，并且它们对两个环的亲和力（CBR ）和外围（PBR）苯并二氮杂receptor受体进行了评估。酯系列化合物对两种受体类型均显示出低亲和力。相反，大多数N，N-二烷基（2-苯基咪唑并[1,2-α吡啶基-3-基]乙酰胺）7e-t对CBR或PBR具有高亲和性和选择性，这取决于C（C 6）-和/或杂环系统上的C（8）。特别是，6-取代的化合物7f-n的IC50值之比（IC50（CBR）/ IC50（PBR））为0.32（7m）至232（7k），而6,8-二取代的化合物7o-t大于PBR的选择性是CBR的1000倍。检查了几种不同的苯二氮卓类