N-(3-chloro-4-(2,5-dioxo-3-phenylpyrrolidin-1-yl)phenyl)picolinamide | 1218926-48-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-chloro-4-(2,5-dioxo-3-phenylpyrrolidin-1-yl)phenyl)picolinamide
• 英文别名: N-[3-chloro-4-(2,5-dioxo-3-phenylpyrrolidin-1-yl)phenyl]pyridine-2-carboxamide
• CAS: 1218926-48-7
• 化学式: C₂₂H₁₆ClN₃O₃
• 分子量: 405.84
• InChiKey: UYGDCIXFYIWDMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  79.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N,N-二boc-2-氯-4-硝基苯胺 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 、 甲苯 为溶剂， 150.0 ℃ 、101.33 kPa 条件下， 反应 25.75h， 生成 N-(3-chloro-4-(2,5-dioxo-3-phenylpyrrolidin-1-yl)phenyl)picolinamide
  参考文献：
  名称：

  Discovery, Synthesis, and Structure–Activity Relationship Development of a Series of N-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄) with Oral Efficacy in an Antiparkinsonian Animal Model

  摘要：

  There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.

  DOI：

  10.1021/jm200956q

文献信息

• [EN] PHTHALIMIDE DERIVATIVE METABOTROPIC GLUTAMATE R4 LIGANDS<br/>[FR] LIGANDS DU GLUTAMATE MÉTABOTROPIQUE R4 DÉRIVÉ DE PHTALAMIDE
  申请人：MERCK & CO INC

  公开号：WO2010033349A1

  公开（公告）日：2010-03-25

  Disclosed are mGluR4 positive allosteric modulator ligands of general formula (I) and radiolabeled derivates, their use as therapeutic agents for the treatment of central nervous system disorders modulated by mGluR4 and as ligands for the labeling and diagnostic imaging of mGluR4 in mammals.

  本文披露了一般式（I）的mGluR4阳性变构调节剂配体以及放射标记衍生物，它们被用作治疗中枢神经系统疾病的治疗剂，这些疾病受mGluR4调节，并且作为哺乳动物中mGluR4的标记和诊断成像的配体。
• SUBSTITUTED DIOXOPIPERIDINES AND DIOXOPYRROLIDINES AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOSITIONS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION
  申请人：Conn P. Jeffrey

  公开号：US20110124663A1

  公开（公告）日：2011-05-26

  In one aspect, the invention relates to compounds having a general structure: wherein the variables are defined herein, which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; 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. 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，该发明涉及具有一般结构的化合物：其中变量如本文所定义，这些化合物可用作代谢型谷氨酸受体亚型4（mGluR4）的变构增强剂/正变构调节剂；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的方法，例如在治疗神经和精神障碍或其他与谷氨酸功能障碍相关的疾病状态中。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。
• PHTHALIMIDE DERIVATIVE METABOTROPIC GLUTAMATE R4 LIGANDS
  申请人：McCauley John A.

  公开号：US20110318266A1

  公开（公告）日：2011-12-29

  Disclosed are mGluR4 positive allosteric modulator ligands of general formula (I) and radiolabeled derivates, their use as therapeutic agents for the treatment of central nervous system disorders modulated by mGluR4 and as ligands for the labeling and diagnostic imaging of mGluR4 in mammals.

  本发明揭示了通式（I）的mGluR4阳性变构调节剂配体和放射性标记衍生物，它们可作为治疗中枢神经系统疾病的治疗剂，这些疾病受mGluR4调节，同时也可作为哺乳动物体内mGluR4的标记和诊断成像的配体。
• US8759377B2
  申请人：——

  公开号：US8759377B2

  公开（公告）日：2014-06-24
• Discovery, Synthesis, and Structure–Activity Relationship Development of a Series of <i>N</i>-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄) with Oral Efficacy in an Antiparkinsonian Animal Model
  作者：Carrie K. Jones、Darren W. Engers、Analisa D. Thompson、Julie R. Field、Anna L. Blobaum、Stacey R. Lindsley、Ya Zhou、Rocco D. Gogliotti、Satyawan Jadhav、Rocio Zamorano、Jim Bogenpohl、Yoland Smith、Ryan Morrison、J. Scott Daniels、C. David Weaver、P. Jeffrey Conn、Craig W. Lindsley、Colleen M. Niswender、Corey R. Hopkins

  DOI：10.1021/jm200956q

  日期：2011.11.10

  There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.