methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate | 1398511-36-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并吡啶类
• 英文名称: methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
• 英文别名: Methyl 6-(hydroxymethyl)pyrazolo[1,5-A]pyridine-3-carboxylate
• CAS: 1398511-36-8
• 化学式: C₁₀H₁₀N₂O₃
• 分子量: 206.201
• InChiKey: WABLOUQYVDBAOU-UHFFFAOYSA-N

物化性质

• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  63.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate 在 水 、 sodium hydride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 13.25h， 生成 6-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
  参考文献：
  名称：

  [EN] (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)METHANONE DERIVATIVES AS MUTANT PAH STABILIZERS FOR THE TREATMENT OF PHENYLKETONURIA
  [FR] DÉRIVÉS DE (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)MÉTHANONE UTILISÉS EN TANT QUE STABILISATEURS DE PAH MUTANTE POUR TRAITER LA PHÉNYLCÉTONURIE

  摘要：

  The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.

  公开号：

  WO2023164233A1
• 作为产物：
  描述：

  methyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate 在 甲醇 、 sodium tetrahydroborate 作用下， 以 四氢呋喃 为溶剂， 以94.9 %的产率得到methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
  参考文献：
  名称：

  [EN] (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)METHANONE DERIVATIVES AS MUTANT PAH STABILIZERS FOR THE TREATMENT OF PHENYLKETONURIA
  [FR] DÉRIVÉS DE (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)MÉTHANONE UTILISÉS EN TANT QUE STABILISATEURS DE PAH MUTANTE POUR TRAITER LA PHÉNYLCÉTONURIE

  摘要：

  The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.

  公开号：

  WO2023164233A1

文献信息

• Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders
  作者：Satoshi Mikami、Shigekazu Sasaki、Yasutomi Asano、Osamu Ujikawa、Shoji Fukumoto、Kosuke Nakashima、Hideyuki Oki、Naomi Kamiguchi、Haruka Imada、Hiroki Iwashita、Takahiko Taniguchi

  DOI：10.1021/acs.jmedchem.7b00709

  日期：2017.9.28

  Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing

  在本文中，我们描述了一种有效的，选择性的，可穿透脑的，体内活性磷酸二酯酶（PDE）2A抑制剂前导系列的发现。为了鉴定适合优化的高质量潜在客户并能够验证体内PDE2A的生理功能，对高通量筛选命中18进行了结构修饰。我们的潜在客户开发工作揭示了三个关键的效能增强功能，即分子量（MW）的增加最小，拓扑极性表面积（TPSA）不变。结合这些结构元素导致鉴定出6-甲基-N -（（（1 R）-1-（4-（三氟甲氧基）苯基）丙基）吡唑并[1,5- a ]嘧啶-3-羧酰胺（38a），具有临床前特性所需平衡的分子。通过与PDE2A结合的38a的共晶体结构分析进一步表征，揭示了独特的结合模式，并提供了对其所观察到的效价和PDE选择性的深入了解。口服后，化合物38a会显着提高小鼠大脑中3'，5'-环鸟苷单磷酸（cGMP）的水平，因此证实该化合物可作为有用的药理学工具和未来优化的引人注目的线索。
• [EN] (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)METHANONE DERIVATIVES AS MUTANT PAH STABILIZERS FOR THE TREATMENT OF PHENYLKETONURIA<br/>[FR] DÉRIVÉS DE (4-BENZO[D]OXAZOL-2-YL)-6,7-DIHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE-5(4H)-YL)MÉTHANONE UTILISÉS EN TANT QUE STABILISATEURS DE PAH MUTANTE POUR TRAITER LA PHÉNYLCÉTONURIE
  申请人：[en]AGIOS PHARMACEUTICALS, INC.

  公开号：WO2023164233A1

  公开（公告）日：2023-08-31

  The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.