5-(4-bromobutoxy)pyrazolo[1,5-a]pyridine | 1060724-84-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并吡啶类
• 英文名称: 5-(4-bromobutoxy)pyrazolo[1,5-a]pyridine
• CAS: 1060724-84-6
• 化学式: C₁₁H₁₃BrN₂O
• 分子量: 269.141
• InChiKey: DCESFCGYNHXFON-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：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  26.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-(4-bromobutoxy)pyrazolo[1,5-a]pyridine 在 sodium iodide 、 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 6.5h， 生成 5-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}pyrazolo[1,5-a]pyridine-3-carbaldehyde
  参考文献：
  名称：

  Functionally Selective Dopamine D₂, D₃Receptor Partial Agonists

  摘要：

  Dopamine D-2 receptor-promoted activation of G alpha(o) over G alpha(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K-i values were determined for D-2L, D-2S, and D-3 receptors. Measurement of [S-35]GTP gamma S incorporation at D-2S coexpressed with G-protein subunits indicated significant bias for promotion of G alpha(o1) over G alpha(i2) coupling for several test compounds. Functionally selective D-2S activation was most striking for the carbaldoxime 8b (G alpha(o1), pEC(50) = 8.87, E-max = 65%; G alpha(i2), pEC(50) = 6.63, E-max = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for beta-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over beta-arrestin-2 recruitment at D-2S receptors. Ligand efficacy and selectivity between D-2S and D-3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.

  DOI：

  10.1021/jm5004039
• 作为产物：
  描述：

  methyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate 在 氢溴酸 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 5-(4-bromobutoxy)pyrazolo[1,5-a]pyridine
  参考文献：
  名称：

  Functionally Selective Dopamine D₂, D₃Receptor Partial Agonists

  摘要：

  Dopamine D-2 receptor-promoted activation of G alpha(o) over G alpha(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K-i values were determined for D-2L, D-2S, and D-3 receptors. Measurement of [S-35]GTP gamma S incorporation at D-2S coexpressed with G-protein subunits indicated significant bias for promotion of G alpha(o1) over G alpha(i2) coupling for several test compounds. Functionally selective D-2S activation was most striking for the carbaldoxime 8b (G alpha(o1), pEC(50) = 8.87, E-max = 65%; G alpha(i2), pEC(50) = 6.63, E-max = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for beta-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over beta-arrestin-2 recruitment at D-2S receptors. Ligand efficacy and selectivity between D-2S and D-3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.

  DOI：

  10.1021/jm5004039

文献信息

• Indolizines and aza-analog derivatives thereof as CNS active compounds
  申请人：SCHWARZ PHARMA AG

  公开号：EP1972628A1

  公开（公告）日：2008-09-24

  Presently disclosed are indolicine-based compounds of the general formula which have medical utility, for example as antipsychotics.

  目前披露的是具有医疗用途的通式为的基于吲哚啉的化合物，例如作为抗精神病药物。
• Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-<i>a</i>]pyridine Substructure
  作者：Dorothee Möller、Ashutosh Banerjee、Taygun C. Uzuneser、Marika Skultety、Tobias Huth、Bianca Plouffe、Harald Hübner、Christian Alzheimer、Kristina Friedland、Christian P. Müller、Michel Bouvier、Peter Gmeiner

  DOI：10.1021/acs.jmedchem.6b01857

  日期：2017.4.13

  moiety to the arylpiperazine core by an appropriate linker represents a promising concept to increase binding affinity and to fine-tune functional properties. In particular, incorporation of a pyrazolo[1,5-a]pyridine heterocyclic appendage led to a series of high-affinity dopamine receptor partial agonists. Comprehensive pharmacological characterization involving BRET biosensors, binding studies, electrophysiology

  1,4-二取代的芳族哌嗪是由胺能G蛋白偶联受体识别的优先结构基序。通过适当的接头将亲脂性部分连接至芳基哌嗪核心代表了增加结合亲和力和微调功能特性的有前途的概念。特别地，吡唑并[1，5- a ]吡啶杂环附件的掺入导致一系列高亲和力的多巴胺受体部分激动剂。涉及BRET生物传感器，结合研究，电生理学和基于互补的测定的综合药理学表征表明，与多巴胺D 2处的β-arrestin募集相比，G蛋白质（优选G o）的活化更有利于化合物的活化。受体。对于代表性的2-甲氧基苯基哌嗪16c，证明了设计G蛋白偏向的局部激动剂作为推定的新疗法的可行性，该化合物明确地显示了体内的抗精神病活性。此外，吡唑并[1，5- a ]吡啶附肢与5-羟基-N-丙基-2-氨基四氢联苯胺单元的组合导致平衡或G蛋白偏倚的多巴胺能配体，这取决于头基的立体化学，说明了复杂多巴胺D 2受体的结构-功能选择性关系。
• INDOLIZINES AND AZA-ANALOG DERIVATIVES THEREOF AS CNS ACTIVE COMPOUNDS
  申请人：Gmeiner Peter

  公开号：US20100168125A1

  公开（公告）日：2010-07-01

  The present application relates to indolizine-based compounds of the general formula (I) and aza-analogs thereof, which have medical utility, for example as antipsychotics.

  本申请涉及基于吲哚嗪的化合物的一般式(I)和其氮杂环类似物，这些化合物具有医学效用，例如作为抗精神病药物。
• Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D₂R Agonists
  作者：Barbara Männel、Daniela Dengler、Jeremy Shonberg、Harald Hübner、Dorothee Möller、Peter Gmeiner

  DOI：10.1021/acs.jmedchem.7b00363

  日期：2017.6.8

  By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the beta(2)-adrenoceptor agonists procaterol and BI-167107 (4),, we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroatylhomopiperazines with high dopamine D-2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the. D2R. that are crucial for an active state, leading to the recruitment of beta-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R. and consequently represent biased agonists favoring beta-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by thepresence of an endocyclic H-bond donor.
• [EN] INDOLIZINES AND AZA-ANALOG DERIVATIVES THEREOF AS CNS ACTIVE COMPOUNDS<br/>[FR] INDOLIZINES ET DÉRIVÉS ANALOGUES AZA DE CELLES-CI EN TANT QUE COMPOSÉS ACTIFS SUR LE SYSTÈME NERVEUX CENTRAL
  申请人：SANOL ARZNEI SCHWARZ GMBH

  公开号：WO2008113559A2

  公开（公告）日：2008-09-25

  [EN] The present application relates to indolizine-based compounds of the general formula (I) and aza-analogs thereof, which have medical utility, for example as antipsychotics.
  [FR] La présente invention porte sur des composés à base d'indolizine de la formule générale (I) et sur les analogues aza de ceux-ci, qui ont une utilité médicale, par exemple comme antipsychotiques.