ML375

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: ML375
• 英文别名: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one；(9bS)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydroimidazo[2,1-a]isoindol-5-one
• 化学式: C₂₃H₁₅ClF₂N₂O₂
• 分子量: 424.834
• InChiKey: GXBAKXRLQAPKEE-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ML375 、 3-甲基哌啶 在 2-双环己基膦-2',6'-二甲氧基联苯 、 palladium diacetate 作用下， 以 甲苯 为溶剂， 反应 0.33h， 生成 (9bS)-1-(3,4-difluorobenzoyl)-9b-[4-(3-methylpiperidin-1-yl)phenyl]-2,3-dihydroimidazo[2,1-a]isoindol-5-one
  参考文献：
  名称：

  Continued optimization of the M 5 NAM ML375: Discovery of VU6008667, an M 5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies

  摘要：

  This letter describes the continued optimization of M-5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375 has an excessively long elimination half-life in rat (t(1/2) = 80 h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M-5 NAM of comparable potency to ML375, but with a rat t(1/2) of less than 4 h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M-5 NAM, with high CNS penetration, excellent selectivity versus M1-4 and the desired short half-life (t(1/2) = 2.3 h) in rat. (C)2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.02.020
• 作为产物：
  描述：

  3,4-二氟苯甲酰氯 在 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0~40.0 ℃ 、10.0 MPa 条件下， 反应 2.12h， 生成 ML375
  参考文献：
  名称：

  Discovery of the First M₅-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)

  摘要：

  A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M-5 subtype. ML375 is a highly selective M-5 NAM with submicromolar potency (human M-5 IC50 = 300 nM, rat M-5 IC50 = 790 nM, M1-M4 IC50 > 30 mu M), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

  DOI：

  10.1021/jm4013246