6-[[[(S)-(3-氟-2-吡啶基)[3-氟-4-(三氟甲氧基)苯基]甲基]氨基]羰基]-3-吡啶甲酸 | 1416799-28-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 6-[[[(S)-(3-氟-2-吡啶基)[3-氟-4-(三氟甲氧基)苯基]甲基]氨基]羰基]-3-吡啶甲酸
• 英文名称: (S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic acid
• 英文别名: Amg 333；6-[[(S)-(3-fluoropyridin-2-yl)-[3-fluoro-4-(trifluoromethoxy)phenyl]methyl]carbamoyl]pyridine-3-carboxylic acid
• CAS: 1416799-28-4
• 化学式: C₂₀H₁₂F₅N₃O₄
• 分子量: 453.325
• InChiKey: QEBYISWYMFIXOZ-INIZCTEOSA-N

物化性质

• 溶解度：
  二甲基亚砜：≥125 mg/ml（275.74mM）

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  11

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  室温

制备方法与用途

生物活性

AMG-333是有效的、高选择性的TRPM8拮抗剂，对人源TRPM8和大鼠TRPM8的IC50值分别为13 nM和30 nM。

Target	Value
human TRPM8	13 nM
rat TRPM8	30 nM

反应信息

• 作为产物：
  描述：

  3-氟吡啶 在 三乙烯二胺 、 盐酸 、 正丁基锂 、 lithium hydroxide monohydrate 、 copper(II) sulfate 、 magnesium 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.5h， 生成 6-[[[(S)-(3-氟-2-吡啶基)[3-氟-4-(三氟甲氧基)苯基]甲基]氨基]羰基]-3-吡啶甲酸
  参考文献：
  名称：

  Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine

  摘要：

  Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a non-selective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

  DOI：

  10.1021/acs.jmedchem.8b00518

文献信息

• TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
  申请人：Biswas Kaustav

  公开号：US20130157996A1

  公开（公告）日：2013-06-20

  Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

  公式I的化合物可用作TRPM8的拮抗剂。这些化合物在治疗许多TRPM8介导的疾病和病症方面非常有用，并可用于制备用于治疗此类疾病和病症的药物和制剂。此类疾病的示例包括但不限于偏头痛和神经病性疼痛。公式I的化合物具有以下结构：其中变量的定义在此提供。
• TRPM8 antagonists and their use in treatments
  申请人：Chen Jian J.

  公开号：US08710043B2

  公开（公告）日：2014-04-29

  Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

  式I的化合物可作为TRPM8拮抗剂使用。这些化合物可用于治疗多种TRPM8介导的疾病和症状，并可用于制备治疗此类疾病和症状的药物和制剂。这些疾病的例子包括但不限于偏头痛和神经病性疼痛。式I的化合物具有以下结构：其中变量的定义在此提供。
• Compositions for treating or preventing vasomotor symptoms
  申请人：Mitsubishi Tanabe Pharma Corporation

  公开号：US10993939B2

  公开（公告）日：2021-05-04

  The present disclosure is directed to compositions and methods for treating or preventing vasomotor symptoms such as hot flashes, comprising a Transient Receptor Potential Melastatin 8 (TRPM8) antagonist and administering a TRPM8 antagonist, respectively.

  本公开涉及用于治疗或预防潮热等血管运动症状的组合物和方法，分别包括瞬时受体电位美拉辛8（TRPM8）拮抗剂和给药TRPM8拮抗剂。
• COMPOSITIONS FOR TREATING OR PREVENTING VASOMOTOR SYMPTOMS
  申请人：Mitsubishi Tanabe Pharma Corporation

  公开号：EP3468557A1

  公开（公告）日：2019-04-17
• US8710043B2
  申请人：——

  公开号：US8710043B2

  公开（公告）日：2014-04-29