2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one
• 英文别名: mGlu5 PAM U0462054；2-(phenoxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyridin-4-one
• 化学式: C₁₄H₁₄N₂O₂
• 分子量: 242.277
• InChiKey: ZFWHPXUPLYPULM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one 在 sodium tetrahydroborate 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 4.0h， 生成 5,5-dimethyl-2-(phenoxymethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyridin-4-ol
  参考文献：
  名称：

  Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

  摘要：

  We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.087
• 作为产物：
  描述：

  苯氧基丙酮 在 potassium tert-butylate 、 sodium ethanolate 、 potassium carbonate 、 lithium chloride 、 肼 作用下， 以 乙醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 32.5h， 生成 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one
  参考文献：
  名称：

  Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

  摘要：

  We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.087

文献信息

• Heterotropic Activation of the Midazolam Hydroxylase Activity of CYP3A by a Positive Allosteric Modulator of mGlu₅: In Vitro to In Vivo Translation and Potential Impact on Clinically Relevant Drug-Drug Interactions
  作者：Anna L. Blobaum、Thomas M. Bridges、Frank W. Byers、Mark L. Turlington、Margrith E. Mattmann、Ryan D. Morrison、Claire Mackie、Hilde Lavreysen、José M. Bartolomé、Gregor J. MacDonald、Thomas Steckler、Carrie K. Jones、Colleen M. Niswender、P. Jeffrey Conn、Craig W. Lindsley、Shaun R. Stauffer、J. Scott Daniels

  DOI：10.1124/dmd.113.052662

  日期：2013.12

  Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu5 PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V max (minimal change in K m) and required the presence of cytochrome b 5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation.

  G蛋白偶联受体的别构调节在药物发现领域引起了相当大的关注，因为这为实现比正位配体更大的选择性打开了途径。我们最近鉴定出一系列对代谢型谷氨酸受体5（mGlu5）的正别构调节剂（PAM），用于治疗精神分裂症，并显示出对CYP3A4酶活性的强大异源激活。该系列的原型化合物5-(4-氟苯甲基)-2-((3-氟苯氧基)methyl)-4,5,6,7-四氢吡唑[1,5-a]吡唑（VU0448187）在体外被发现可激活CYP3A4至其基础内源性咪达唑仑（MDZ）羟化酶活性的>100%；该激活是CYP3A底物特异性的，并且依赖于mGlu5 PAM。额外研究揭示了VU0448187在多种物种的肝脏和肠道微粒体及肝细胞中对CYP3A激活的浓度依赖性，以及在有酮康唑存在时观察到的效应减弱。对VU0448187在重组P450或人肝微粒子中对MDZ代谢影响的动力学分析显示，Vmax显著增加（K m变化较小），并且需要细胞色素b5的存在。由于这些非典型动力学现象的转化，接受VU0448187腹腔注射的老鼠在MDZ治疗前与单独给予MDZ的老鼠相比，循环中1-和4-羟基咪达唑仑（1-OH-MDZ, 4-OH-MDZ）水平显著增加。发现了一种在体外到体内转化的强效底物选择激活剂，强调了提高小鼠肝脏及肝外CYP3A内源性酶活性的影响，并为构建能够框定底物依赖的异源性激活的临床相关性的模型提供了基础。
• BICYCLIC TRIAZOLE AND PYRAZOLE LACTAMS AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
  申请人：Conn P. Jeffrey

  公开号：US20120225844A1

  公开（公告）日：2012-09-06

  In one aspect, the invention relates to bicyclic triazole and pyrazole lactams, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及双环三唑和吡唑内酰胺、其衍生物和相关化合物，可作为代谢型谷氨酸受体亚型5（mGluR5）的正向变构调节剂；制备这些化合物的合成方法；包含这些化合物的制药组合物；以及使用这些化合物和组合物治疗与谷氨酸功能障碍相关的神经和精神障碍的方法。本摘要旨在作为特定领域搜索的扫描工具，不限制本发明。
• Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency
  作者：Mark Turlington、Meredith J. Noetzel、Thomas M. Bridges、Paige N. Vinson、Thomas Steckler、Hilde Lavreysen、Claire Mackie、José M. Bartolomé-Nebreda、Susana Conde-Ceide、Han Min Tong、Gregor J. Macdonald、J. Scott Daniels、Carrie K. Jones、Colleen M. Niswender、P. Jeffrey Conn、Craig W. Lindsley、Shaun R. Stauffer

  DOI：10.1016/j.bmcl.2014.04.087

  日期：2014.8

  We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series. (C) 2014 Elsevier Ltd. All rights reserved.