(R)-6-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)pyridazine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-6-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)pyridazine-3-carboxamide
• 英文别名: 6-[2-(3-fluorophenyl)ethynyl]-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]pyridazine-3-carboxamide
• 化学式: C₁₈H₁₈FN₃O₂
• 分子量: 327.358
• InChiKey: AZRUYFVGHLIIFR-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  75.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-甲基-2-丙基[(2R)-3-羟基-3-甲基-2-丁烷基]氨基甲酸酯 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.17h， 生成 (R)-6-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)pyridazine-3-carboxamide
  参考文献：
  名称：

  Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

  摘要：

  Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu(5) PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu(5) PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift similar to 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu(5) PAMs.

  DOI：

  10.1021/jm401028t