N-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine
• 英文别名: valiglurax；VU2957；Valiglurax；N-(2H-pyrazolo[3,4-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine
• 化学式: C₁₆H₁₀F₃N₅
• 分子量: 329.284
• InChiKey: RUEXKBWCUUFJMY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-溴异喹啉 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 caesium carbonate 、 间氯过氧苯甲酸 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 甲苯 为溶剂， 反应 0.55h， 生成 N-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine
  参考文献：
  名称：

  [EN] ISOQUINILINE AND NAPTHALENE-SUBSTITUTED COMPOUNDS AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOUNDS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION
  [FR] COMPOSÉS À SUBSTITUTION ISOQUINILINE AND NAPTHALENE UTILES EN TANT QUE POTENTIALISATEURS ALLOSTÉRIQUES DE MGLUR4, COMPOSÉS, ET MÉTHODES DE TRAITEMENT DE TROUBLES NEUROLOGIQUES

  摘要：

  翻译结果为：对代谢性谷氨酸受体4型（mGluR4）具有激动作用/正向变构调节作用的化合物；包含这些化合物的药物组合物；以及使用这些化合物的方法，例如，用于治疗与谷氨酸功能障碍相关的神经和精神障碍或其他疾病状态。

  公开号：

  WO2016123627A1

文献信息

• [EN] ISOQUINILINE AND NAPTHALENE-SUBSTITUTED COMPOUNDS AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOUNDS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION<br/>[FR] COMPOSÉS À SUBSTITUTION ISOQUINILINE AND NAPTHALENE UTILES EN TANT QUE POTENTIALISATEURS ALLOSTÉRIQUES DE MGLUR4, COMPOSÉS, ET MÉTHODES DE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：UNIV VANDERBILT

  公开号：WO2016123627A1

  公开（公告）日：2016-08-04

  Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.

  翻译结果为：对代谢性谷氨酸受体4型（mGluR4）具有激动作用/正向变构调节作用的化合物；包含这些化合物的药物组合物；以及使用这些化合物的方法，例如，用于治疗与谷氨酸功能障碍相关的神经和精神障碍或其他疾病状态。
• Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
  申请人：Vanderbilt University

  公开号：US10227343B2

  公开（公告）日：2019-03-12

  Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.

  可用作代谢型谷氨酸受体亚型 4（mGluR4）的异位增效剂/阳性异位调节剂的化合物；包含这些化合物的药物组合物；以及使用这些化合物的方法，例如，治疗神经和精神疾病或与谷氨酸功能障碍相关的其他疾病状态的方法。
• The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
  作者：Joseph D. Panarese、Darren W. Engers、Yong-Jin Wu、Jason M. Guernon、Aspen Chun、Alison R. Gregro、Aaron M. Bender、Rory A. Capstick、Joshua M. Wieting、Joanne J. Bronson、John E. Macor、Ryan Westphal、Matthew Soars、Julie E. Engers、Andrew S. Felts、Alice L. Rodriguez、Kyle A. Emmitte、Carrie K. Jones、Anna L. Blobaum、P. Jeffrey Conn、Colleen M. Niswender、Corey R. Hopkins、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2018.10.050

  日期：2019.1

  This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu(4) positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
• ISOQUINILINE AND NAPTHALENE-SUBSTITUTED COMPOUNDS AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOSITIONS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION
  申请人：Vanderbilt University

  公开号：US20180022745A1

  公开（公告）日：2018-01-25

  Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.
• Discovery of VU2957 (Valiglurax): An mGlu₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease
  作者：Joseph D. Panarese、Darren W. Engers、Yong-Jin Wu、Joanne J. Bronson、John E. Macor、Aspen Chun、Alice L. Rodriguez、Andrew S. Felts、Julie L. Engers、Matthew T. Loch、Kyle A. Emmitte、Arlindo L. Castelhano、Michael J. Kates、Michael A. Nader、Carrie K. Jones、Anna L. Blobaum、P. Jeffrey Conn、Colleen M. Niswender、Corey R. Hopkins、Craig W. Lindsley

  DOI：10.1021/acsmedchemlett.8b00426

  日期：2019.3.14

  Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mG1u4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.