4-{5-[2-(4,4-difluoropiperidin-1-yl)-5-methanesulfonylbenzoyl]-2H,4H,5H, 6H-pyrrolo[3,4-c]pyrazol-2-yl}-2-methylpyridine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-{5-[2-(4,4-difluoropiperidin-1-yl)-5-methanesulfonylbenzoyl]-2H,4H,5H, 6H-pyrrolo[3,4-c]pyrazol-2-yl}-2-methylpyridine
• 英文别名: [2-(4,4-Difluoropiperidin-1-yl)-5-methylsulfonylphenyl]-[2-(2-methylpyridin-4-yl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl]methanone；[2-(4,4-difluoropiperidin-1-yl)-5-methylsulfonylphenyl]-[2-(2-methylpyridin-4-yl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl]methanone
• 化学式: C₂₄H₂₅F₂N₅O₃S
• 分子量: 501.557
• InChiKey: UVGRMAGENRJKRM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  96.8
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-氟-5-甲烷磺酰基苯甲酸 在 氯化亚砜 、 caesium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 26.92h， 生成 4-{5-[2-(4,4-difluoropiperidin-1-yl)-5-methanesulfonylbenzoyl]-2H,4H,5H, 6H-pyrrolo[3,4-c]pyrazol-2-yl}-2-methylpyridine
  参考文献：
  名称：

  Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

  摘要：

  We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4-c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebro-spinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

  DOI：

  10.1021/acs.jmedchem.8b00372

文献信息

• SUBSTITUTED 2,4,5,6-TETRAHYDROPYRROLO[3,4-C]PYRAZOLE AND 4,5,6,7-TETRAHYDRO-2H-PYRAZOLO[4,3-C]PYRIDINE COMPOUNDS AS GLYT1 INHIBITORS
  申请人：DART NEUROSCIENCE (CAYMAN) LTD.

  公开号：US20170044167A1

  公开（公告）日：2017-02-16

  The invention provides a chemical entity of Formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 and X have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by GlyT1 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training; and treating other disorders, including pain and alcohol-dependence.
• US9708334B2
  申请人：——

  公开号：US9708334B2

  公开（公告）日：2017-07-18
• [EN] SUBSTITUTED 2,4,5,6-TETRAHYDROPYRROLO[3,4-C] PYRAZOLE AND 4,5,6,7-TETRAHYDRO-2H-PYRAZOLO [4,3-C] PYRIDINE COMPOUNDS AS GLYT1 INHIBITORS<br/>[FR] COMPOSÉS DE 2,4,5,6-TÉTRAHYDROPYRROLO[3,4-C] PYRAZOLE ET 4,5,6,7-TÉTRAHYDRO-2 H-PYRAZOLO [4,3-C] PYRIDINE UTILISÉS COMME INHIBITEURS DE GLYT1
  申请人：DART NEUROSCIENCE LLC

  公开号：WO2015164520A1

  公开（公告）日：2015-10-29

  The invention provides a chemical entity of Formula (I), wherein R1, R2, R3, R4, R5 and X have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by GlyT1 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training; and treating other disorders, including pain and alcohol-dependence.
• Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties
  作者：Vincent J. Santora、Theresa A. Almos、Richard Barido、Jillian Basinger、Chris L. Bellows、Brett C. Bookser、J. Guy Breitenbucher、Nicola J. Broadbent、Clifford Cabebe、Chih-Kun Chai、Mi Chen、Stephine Chow、De Michael Chung、Lindsay Crickard、Anne M. Danks、Graeme C. Freestone、Dany Gitnick、Varsha Gupta、Christine Hoffmaster、Andrew R. Hudson、Alan P. Kaplan、Michael R. Kennedy、Dong Lee、James Limberis、Kiev Ly、Chi Ching Mak、Brittany Masatsugu、Andrew C. Morse、Jim Na、David Neul、John Nikpur、Marco Peters、Robert E. Petroski、Joel Renick、Kristen Sebring、Samantha Sevidal、Ali Tabatabaei、Jenny Wen、Yingzhuo Yan、Zachary W. Yoder、Douglas Zook

  DOI：10.1021/acs.jmedchem.8b00372

  日期：2018.7.26

  We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4-c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebro-spinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.