VU0486846 | 1788055-11-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: VU0486846
• 英文别名: (2R)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyrazol-1-ylphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-2-carboxamide
• CAS: 1788055-11-7
• 化学式: C₂₅H₂₈N₄O₃
• 分子量: 432.522
• InChiKey: LZCHTDQRMCSDSE-ODGPQVTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  79.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,4-二氢-2H-苯并[1,4]噁嗪-2-羧酸乙酯 在 水 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.33h， 生成 VU0486846 、 (2S)-4-(4-(1H-pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide
  参考文献：
  名称：

  [EN] SUBSTITUTED 4-BENZYL-3,4-DIHYDRO-2H-BENZO[B][1,4]OXAZINE-2CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF MUSCARINIC ACETYCHOLINE RECEPTOR M1
  [FR] ANALOGUES SUBSTITUÉS DU 4-BENZYL-3,4-DIHYDRO-2H-BENZO[B] [1,4] OXAZINE-2-CARBOXAMIDE, UTILISÉS COMME MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M1

  摘要：

  在一个方面，这项发明涉及N-取代的3,4-二氢苯并[£][1,4]噁嗪-2-羧酰胺类似物，其衍生物和相关化合物，这些化合物可用作肌胆碱受体M1（mAChR M1）的正向变构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与肌胆碱受体功能障碍相关的神经和精神疾病的方法。本摘要旨在作为在特定领域搜索的扫描工具，并不意味着对本发明的限制。

  公开号：

  WO2015080904A1

文献信息

• [EN] SUBSTITUTED 4-BENZYL-3,4-DIHYDRO-2H-BENZO[B][1,4]OXAZINE-2CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF MUSCARINIC ACETYCHOLINE RECEPTOR M1<br/>[FR] ANALOGUES SUBSTITUÉS DU 4-BENZYL-3,4-DIHYDRO-2H-BENZO[B] [1,4] OXAZINE-2-CARBOXAMIDE, UTILISÉS COMME MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M1
  申请人：UNIV VANDERBILT

  公开号：WO2015080904A1

  公开（公告）日：2015-06-04

  In one aspect, the invention relates to N-substituted 3,4-dihydro-benzo[£][l,4]oxazine-2-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，这项发明涉及N-取代的3,4-二氢苯并[£][1,4]噁嗪-2-羧酰胺类似物，其衍生物和相关化合物，这些化合物可用作肌胆碱受体M1（mAChR M1）的正向变构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与肌胆碱受体功能障碍相关的神经和精神疾病的方法。本摘要旨在作为在特定领域搜索的扫描工具，并不意味着对本发明的限制。
• SUBSTITUTED 4-BENZYL-3,4-DIHYDRO-2H-BENZO[B][1,4]OXAZINE-2CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF MUSCARINIC ACETYCHOLINE RECEPTOR M1
  申请人：Vanderbilt University

  公开号：US20170022173A1

  公开（公告）日：2017-01-26

  In one aspect, the invention relates to N-substituted 3,4-dihydro-benzo[£][1,4]oxazine-2-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 1 (mAChR M 1 ); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
• US9708278B2
  申请人：——

  公开号：US9708278B2

  公开（公告）日：2017-07-18
• A Novel M₁ PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity
  作者：Jerri M. Rook、Jeanette L. Bertron、Hyekyung P. Cho、Pedro M. Garcia-Barrantes、Sean P. Moran、James T. Maksymetz、Kellie D. Nance、Jonathan W. Dickerson、Daniel H. Remke、Sichen Chang、Joel M. Harp、Anna L. Blobaum、Colleen M. Niswender、Carrie K. Jones、Shaun R. Stauffer、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1021/acschemneuro.8b00131

  日期：2018.9.19

  Selective activation of the M-1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M-1, ago-PAM5, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M-1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M-1 PAM, VU0486846. VU0486846 possesses only weak agonist activity in M-1-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [H-3]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M-1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M-1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M-1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.