(1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl 4-methylbenzenesulfonate | 1346569-63-8

• 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: (1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl 4-methylbenzenesulfonate
• 英文别名: {1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[3,2-b]pyridin-5-yl}methyl 4-methylbenzenesulfonate
• CAS: 1346569-63-8
• 化学式: C₂₂H₂₀N₂O₅S₂
• 分子量: 456.543
• InChiKey: MXEDTALRHOZLID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  95.33
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl 4-methylbenzenesulfonate 在 硫酸 、 caesium carbonate 、 sodium nitrite 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.17h， 生成
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists

  摘要：

  We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (C-max = 44 ng/mL; AUC(0-t), = 359 ng.h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (C-max = 359 ng.h/mL; AUC(0-t), = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.

  DOI：

  10.1021/acs.jmedchem.5b01240
• 作为产物：
  描述：

  ethyl 5-amino-6-((trimethylsilyl)ethynyl)picolinate 在 吡啶 、 lithium aluminium tetrahydride 、 四丁基氟化铵 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 12.17h， 生成 (1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl 4-methylbenzenesulfonate
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists

  摘要：

  We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (C-max = 44 ng/mL; AUC(0-t), = 359 ng.h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (C-max = 359 ng.h/mL; AUC(0-t), = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.

  DOI：

  10.1021/acs.jmedchem.5b01240

文献信息

• [EN] ARYL SUBSTITUTED OLEFINIC COMPOUNDS AS PDE10A INHIBITORS<br/>[FR] COMPOSÉS OLÉFINIQUES À SUBSTITUTION ARYLE EN TANT QU'INHIBITEURS DE LA PDE10A
  申请人：GLENMARK PHARMACEUTICALS SA

  公开号：WO2011138657A1

  公开（公告）日：2011-11-10

  The present invention provides aryl substituted olefinic compounds as Phosphodiesterase 1 0A (PDE 1 0A) inhibitors. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders by inhibiting Phosphodiesterase 1 0A enzyme. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof.

  本发明提供了芳基取代烯烃化合物作为磷酸二酯酶1 0A（PDE 1 0A）抑制剂。具体来说，本文描述的化合物可用于通过抑制磷酸二酯酶1 0A酶来治疗或预防疾病、症状和/或紊乱。本文还提供了用于制备本文描述的化合物的工艺、用于合成的中间体以及它们的药物组合物。