2-[(1R,2S)-2-(5-hydroxypyridin-3-yl)cyclopropyl]ethyl isobutyrate | 1355996-42-7

• 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: 2-[(1R,2S)-2-(5-hydroxypyridin-3-yl)cyclopropyl]ethyl isobutyrate
• CAS: 1355996-42-7
• 化学式: C₁₄H₁₉NO₃
• 分子量: 249.31
• InChiKey: FABROSJXWHMIIM-GWCFXTLKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.48
• 重原子数：
  18.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  59.42
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-[(1R,2S)-2-(5-hydroxypyridin-3-yl)cyclopropyl]ethyl isobutyrate 在 甲醇 、 三丁基膦 、 sodium methylate 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 甲苯 为溶剂， 反应 6.0h， 生成 2-[(1R,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol
  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
• 作为产物：
  描述：

  trans-3-[5-(benzyloxy)-3-pyridyl]acrylic acid 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 硼烷四氢呋喃络合物 、 草酰氯 、 palladium 10% on activated carbon 、 氢气 、 sodium hexamethyldisilazane 、 sodium hydride 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 环己烷 、 二甲基亚砜 、 乙酸乙酯 为溶剂， 反应 19.75h， 生成 2-[(1R,2S)-2-(5-hydroxypyridin-3-yl)cyclopropyl]ethyl isobutyrate
  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

• Synthesis and Behavioral Studies of Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part III
  作者：Oluseye K. Onajole、Gian Paolo Vallerini、J. Brek Eaton、Ronald J. Lukas、Dani Brunner、Barbara J. Caldarone、Alan P. Kozikowski

  DOI：10.1021/acschemneuro.6b00050

  日期：2016.6.15

  We report the synthesis and biological characterization of novel derivatives of 3-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-cyclopropylpyridine (4a–f and 5) as potent and highly selective α4β2-nicotinic acetylcholine receptor (nAChR) full or partial agonists. A systematic structure–activity study was carried out on the previously described compound 3b, particularly concerning its (2-methoxyethyl)cyclopropyl

  我们报告了 3-[(1-甲基-2( S )-吡咯烷基)甲氧基]-5-环丙基吡啶 ( 4a – f和5 )的新衍生物的合成和生物学特性，它们是有效和高选择性的 α4β2-烟碱乙酰胆碱受体 ( nAChR) 完全或部分激动剂。对先前描述的化合物3b进行了系统的结构-活性研究，特别是关于其（2-甲氧基乙基）环丙基侧链，以努力提高其代谢稳定性，同时保持受体选择性。与3b相比，化合物4d对 α4β2- 和 α4β2*-nAChR 表现出非常相似的亚纳摩尔结合亲和力，并且它在激活高敏 (HS) α4β2-nAChRs 方面表现出优异的效力，EC 50值为 8.2 nM。在 SmartCube 分析中对4d的测试表明，该化合物具有联合抗抑郁药和抗精神病药的特征。在腹膜内给予 30 mg/kg 剂量的强迫游泳试验中，发现4d与舍曲林一样有效，因此提供了该化合物作为抗抑郁药潜在用途的证据。在人类中使用4d的
• Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands
  作者：Oluseye K. Onajole、J. Brek Eaton、Ronald J. Lukas、Dani Brunner、Lucinda Thiede、Barbara J. Caldarone、Alan P. Kozikowski

  DOI：10.1021/ml500129k

  日期：2014.11.13

  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.