2-(4-Chloro-2-methylphenoxy)pyridine-3-carboxylic acid | 953900-08-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(4-Chloro-2-methylphenoxy)pyridine-3-carboxylic acid
• CAS: 953900-08-8
• 化学式: C₁₃H₁₀ClNO₃
• mdl: MFCD00955269
• 分子量: 263.68
• InChiKey: JKKQLRXESWUKIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.076
• 拓扑面积：
  59.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-Chloro-2-methylphenoxy)pyridine-3-carboxylic acid 在 过氧乙酸 、 碳酸氢钠 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 2-(4-chloro-2-methylphenoxy)-3-(5-methylsulfonyl-1H-1,2,4-triazol-3-yl)pyridine
  参考文献：
  名称：

  1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na V 1.7 inhibition

  摘要：

  Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na(v)1.7 and demonstrate high levels of selectivity over other Na-v isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na(v)1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na v 1.5 and favorable pharmacokinetics in rodents. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2018.04.035
• 作为产物：
  描述：

  2-氯烟酸乙酯 在 水 、 caesium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 为溶剂， 反应 52.0h， 生成 2-(4-Chloro-2-methylphenoxy)pyridine-3-carboxylic acid
  参考文献：
  名称：

  Discovery of a new class of glucosylceramide synthase inhibitors

  摘要：

  A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.037

文献信息

• [EN] GLUCOSYLCERAMIDE SYNTHASE INHIBITORS<br/>[FR] INHIBITEURS DE LA GLUCOSYLCÉRAMIDE SYNTHASE
  申请人：EXELIXIS INC

  公开号：WO2010091104A1

  公开（公告）日：2010-08-12

  The present invention comprises glucosylceramide synthase (GCS) inhibitors of structural formula (I), and pharmaceutically acceptable salts thereof, wherein R1, E, A, L, X1, Q, R4, R5, m and n, are as defined herein, as well as N-oxides of them and pharmaceutically acceptable salts thereof. The invention further comprises composition comprising the compounds, N-oxides, and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which GCS is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is implicated.
• Discovery of a new class of glucosylceramide synthase inhibitors
  作者：Elena Koltun、Steven Richards、Vicky Chan、Jason Nachtigall、Hongwang Du、Kevin Noson、Adam Galan、Naing Aay、Art Hanel、Amanda Harrison、Jeff Zhang、Kwang-Ai Won、Danny Tam、Fawn Qian、Tao Wang、Patricia Finn、Kathleen Ogilvie、Jon Rosen、Raju Mohan、Christopher Larson、Peter Lamb、John Nuss、Patrick Kearney

  DOI：10.1016/j.bmcl.2011.09.037

  日期：2011.11

  A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo. (C) 2011 Elsevier Ltd. All rights reserved.
• 1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na V 1.7 inhibition
  作者：Alessandro A. Boezio、Kristin Andrews、Christiane Boezio、Margaret Chu-Moyer、Katrina W. Copeland、Erin F. DiMauro、Robert S. Foti、Robert T. Fremeau、Hua Gao、Stephanie Geuns-Meyer、Russell F. Graceffa、Hakan Gunaydin、Hongbing Huang、Daniel S. La、Joseph Ligutti、Bryan D. Moyer、Emily A. Peterson、Violeta Yu、Matthew M. Weiss

  DOI：10.1016/j.bmcl.2018.04.035

  日期：2018.6

  Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na(v)1.7 and demonstrate high levels of selectivity over other Na-v isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na(v)1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na v 1.5 and favorable pharmacokinetics in rodents. (C) 2018 Elsevier Ltd. All rights reserved.