3-[[[((1R)-1-(4-氟苯基)乙基](3-喹啉基羰基)氨基]甲基]苯甲酸 | 1398583-31-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 3-[[[((1R)-1-(4-氟苯基)乙基](3-喹啉基羰基)氨基]甲基]苯甲酸
• 英文名称: PF-05105679
• 英文别名: 3-[[[(1R)-1-(4-fluorophenyl)ethyl]-(quinoline-3-carbonyl)amino]methyl]benzoic acid
• CAS: 1398583-31-7
• 化学式: C₂₆H₂₁FN₂O₃
• 分子量: 428.463
• InChiKey: BXNMZRPTQFVRFA-QGZVFWFLSA-N

物化性质

• 沸点：
  669.0±55.0 °C(Predicted)
• 密度：
  1.308±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  70.5
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• WGK Germany：
  3
• 储存条件：
  -20°C

制备方法与用途

PF-05105679 是一种具有口服活性的选择性TRPM8拮抗剂，其IC50值为103 nM。TRPM8，又称为感冒和薄荷醇受体1（CMR1），是褪黑素亚家族成员之一。PF-05105679 在治疗与感冒相关的疼痛方面表现出良好的临床疗效。

反应信息

• 作为产物：
  描述：

  在 水 、 三乙酰氧基硼氢化钠 、 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 2-甲基四氢呋喃 、 甲醇 、 乙酸乙酯 为溶剂， 反应 0.75h， 生成 3-[[[((1R)-1-(4-氟苯基)乙基](3-喹啉基羰基)氨基]甲基]苯甲酸
  参考文献：
  名称：

  Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

  摘要：

  The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 degrees C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

  DOI：

  10.1021/ml500479v

文献信息

• [EN] ARYL SUBSTITUTED CARBOXAMIDE DERIVATIVES AS TRPM8 MODULATORS<br/>[FR] DÉRIVÉS DE CARBOXAMIDE SUBSTITUÉS PAR ARYLE EN TANT QUE MODULATEURS DE TRPM8
  申请人：PFIZER LTD

  公开号：WO2012120398A1

  公开（公告）日：2012-09-13

  The invention provides a compound of the formula (I): wherein A, R1, R2 and R3 are as defined herein, or a pharmaceutically acceptable salt thereof. Such compounds are small molecule TRPM8 blockers and therefore useful in the propylaxis or treatment of a wide range of diseases, conditions or syndromes, including cold allodynia and Raynaulds syndrome.

  本发明提供了一种化合物，其化学式为（I）：其中A、R1、R2和R3如本文所定义，或其药学上可接受的盐。这些化合物是小分子TRPM8阻断剂，因此在预防或治疗包括寒冷痛觉异常和雷诺综合征在内的各种疾病、症状或综合征中有用。
• ACS Medicinal Chemistry Letters 2015, 6, 419-424
  作者：

  DOI：——

  日期：——
• METHODS FOR DETECTING DISORDERS RELATED TO CALCIUM DISCHARGE FROM INTRACELLULAR STORES
  申请人：The Regents of the University of California

  公开号：US20210311075A1

  公开（公告）日：2021-10-07

  Provided herein are methods for determining whether a subject has an increased likelihood of having a disorder related to abnormal intracellular calcium store discharge. In some embodiments, the method is useful for determining whether the subject has an increased likelihood of having a neurodegenerative disease, skeletal muscle disease, cardiac muscle disease, autoimmune disease, cancer, diabetes, or has been exposed to an environmental pollutant. Kits are also provided herein.
• Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain
  作者：Mark D. Andrews、Kerry af Forselles、Kevin Beaumont、Sébastien R. G. Galan、Paul A. Glossop、Mathilde Grenie、Alan Jessiman、Amy S. Kenyon、Graham Lunn、Graham Maw、Robert M. Owen、David C. Pryde、Dannielle Roberts、Thien Duc Tran

  DOI：10.1021/ml500479v

  日期：2015.4.9

  The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 degrees C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.