N-(3-chloro-4-(4-methyl-1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide

• 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-(4-methyl-1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide
• 英文别名: N-[3-chloro-4-(4-methyl-1,3-dioxoisoindol-2-yl)phenyl]-3-methylfuran-2-carboxamide
• 化学式: C₂₁H₁₅ClN₂O₄
• 分子量: 394.814
• InChiKey: HATXMKFRRQUAFD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  79.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-硝基-2-甲苯胺 在 4-二甲氨基吡啶 、 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 生成 N-(3-chloro-4-(4-methyl-1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide
  参考文献：
  名称：

  Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core

  摘要：

  This Letter describes the lead optimization of the VU0486321 series of mGlu(1) positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu(1) PAMs since. New genetic data linking loss-of-function mutant mGlu(1) receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu(4). (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.10.013

文献信息

• Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu₁), Based on an <i>N</i>-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu₁ Receptors Found in Schizophrenics
  作者：Pedro M. Garcia-Barrantes、Hyekyung P. Cho、Colleen M. Niswender、Frank W. Byers、Charles W. Locuson、Anna L. Blobaum、Zixiu Xiang、Jerri M. Rook、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1021/acs.jmedchem.5b00727

  日期：2015.10.22

  The therapeutic potential of selective mGlu(1) activation is vastly unexplored relative to the other group I mGlu receptor, mGlu(5); therefore, our lab has focused considerable effort toward developing mGlu(1) positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu(1) PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu(1) EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (K-p) of 1.02) mGlu(1) PAM tool compound, that potentiated not only wild-type human mGlu(1) but also mutant mGlu(1) receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu(1) ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu(5) ago-PAMs/PANIs and maintain temporal activity suggesting a broader therapeutic window.
• Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core
  作者：Pedro M. Garcia-Barrantes、Hyekyung P. Cho、Anna L. Blobaum、Colleen M. Niswender、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2015.10.013

  日期：2015.11

  This Letter describes the lead optimization of the VU0486321 series of mGlu(1) positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu(1) PAMs since. New genetic data linking loss-of-function mutant mGlu(1) receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu(4). (C) 2015 Elsevier Ltd. All rights reserved.