3-hydroxy-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine | 1222137-86-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-hydroxy-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine
• 英文别名: 5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridin-3-ol
• CAS: 1222137-86-1
• 化学式: C₁₁H₁₅NO₂
• 分子量: 193.246
• InChiKey: IDWWDDDQWJLENI-KWQFWETISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  42.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-hydroxy-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine 在 吡啶 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 0.17h， 生成 cis-2-[5-[(1S,2R)-2-(2-ethoxyethyl)cyclopropyl]pyridin-3-yl]octahydropyrrolo[3,4-c]pyrrole trifluoroacetate
  参考文献：
  名称：

  Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands

  摘要：

  We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR) subtype. Structureactivity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR beta 2 subunit-containing nAChR subtypes (beta 2*-nAChRs) over beta 4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for alpha 4 beta 2- and alpha 4 beta 2*-nAChRs with negligible interaction. Functional assays confirm selectivity for alpha 4 beta 2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15.

  DOI：

  10.1021/ml500129k
• 作为产物：
  描述：

  (±)-trans-2-[5-(benzyloxy)-3-pyridyl]-N-methoxy-N-methylcyclopropanecarboxamide 在 platinum(IV) oxide 、 sodium tetrahydroborate 、 正丁基锂 、 草酰氯 、 palladium 10% on activated carbon 、 氢气 、 二甲基亚砜 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 16.42h， 生成 3-hydroxy-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine
  参考文献：
  名称：

  Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

  摘要：

  Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing alpha 4 beta 2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at alpha 4 beta 2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other alpha 4 beta 2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

  DOI：

  10.1021/jm201157c

文献信息

• NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
  申请人：Chandrasekhar Jayaraman

  公开号：US20130184313A1

  公开（公告）日：2013-07-18

  The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.

  该发明涉及吡啶基烟碱乙酰胆碱受体配体，包含有效量吡啶基烟碱乙酰胆碱受体配体的组合物，以及治疗或预防某种疾病的方法，如抑郁症和尼古丁依赖症，包括向需要的动物施用有效量吡啶基烟碱乙酰胆碱受体配体。
• Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II
  作者：Han-Kun Zhang、Li-Fang Yu、J. Brek Eaton、Paul Whiteaker、Oluseye K. Onajole、Taleen Hanania、Daniela Brunner、Ronald J. Lukas、Alan P. Kozikowski

  DOI：10.1021/jm400510u

  日期：2013.7.11

  A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure–activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering

  最近在我们努力创造新型抗抑郁药时发现了一种带有含环丙烷侧链的 3-吡啶基醚支架，这些抗抑郁药可作为 α4β2-烟碱型乙酰胆碱受体的部分激动剂。在这项研究中，对化合物3 中的氮杂环丁烷部分及其右侧链进行了系统的构效关系研究，从而发现了多种保留生物活性并具有改善的化学稳定性的新型烟碱配体。与母体化合物4和N-甲基吡咯烷类似物相比，最有希望的化合物24、26和30表现出可比或增强的药理学特征26在小鼠强迫游泳试验中也表现出强大的抗抑郁药样功效。有利的 ADMET 特征和26 的化学稳定性进一步表明，该化合物作为候选药物是有希望的，保证了药物发现管道的进一步发展。
• [EN] NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF<br/>[FR] LIGANDS DES RÉCEPTEURS CHOLINERGIQUES NICOTINIQUES ET LEURS UTILISATIONS
  申请人：PSYCHOGENICS INC

  公开号：WO2010045212A3

  公开（公告）日：2010-07-29
• US8445684B2
  申请人：——

  公开号：US8445684B2

  公开（公告）日：2013-05-21