N-[4-[[6-[4-(三氟甲基)苯基]-4-嘧啶基]氧基]-2-苯并噻唑基]乙酰胺 | 659730-32-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: N-[4-[[6-[4-(三氟甲基)苯基]-4-嘧啶基]氧基]-2-苯并噻唑基]乙酰胺
• 中文别名: N-(4-(6-(4-(三氟甲基)苯基)嘧啶-4-基氧基)苯并[d]噻唑-2-基)乙酰胺
• 英文名称: N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl]acetamide
• 英文别名: AMG 517；N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide；N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl]-acetamide；(N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]benzothiazol-2-yl}acetamide)；AMG-517；AMG517；Acetamide, N-(4-((6-(4-(trifluoromethyl)phenyl)-4-pyrimidinyl)oxy)-2-benzothiazolyl)-；N-[4-[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]acetamide
• CAS: 659730-32-2
• 化学式: C₂₀H₁₃F₃N₄O₂S
• 分子量: 430.41
• InChiKey: YUTIXVXZQIQWGY-UHFFFAOYSA-N

物化性质

• 熔点：
  227℃
• 密度：
  1.458
• 溶解度：
  DMSO 中≥21.5 mg/mL；不溶于水；乙醇中≥4.93 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  9

安全信息

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

制备方法与用途

生物活性

AMG-517是一种有效的、选择性的TRPV1拮抗剂，能够抑制由辣椒素、质子和热激活的TRPV1，IC50值分别为0.76 nM、0.62 nM和1.3 nM。

靶点

Target	Value
TRPV1	1 nM-2 nM

体外研究

AMG 517能够抑制由500 nM辣椒素、pH 5.0的酸或45°C的热诱导的反应。

体内研究

口服处理AMG 517后，血浆浓度增加，并且这种作用表现出剂量依赖性。该处理也降低了Capsaicin处理引起的血块收缩数量，同样表现为剂量依赖性。根据统计分析显示，在对照组和Capsaicin实验组之间退缩数量的显著差异表明，AMG 517的最低有效剂量（MED）为0.3 mg/kg。相应地，其血浆浓度范围在90至100 ng/mL。

24小时后，3 mg/kg的AMG 517处理显著减少了由Capsaicin引起的退缩。此外，在CFA疼痛模型中，AMG 517抑制了热痛觉过敏。值得注意的是，在啮齿类动物、狗和猴子中观察到AMG 517的效果，但TRPV1基因敲除的小鼠没有反应。

有趣的是，对于TRPV1选择性拮抗剂诱发的体温过高现象，通过重复给药大鼠、狗、猴以及TRPV1基因敲除小鼠后，这种高体温反应可以减弱，体温不会降低。

反应信息

• 作为反应物：
  描述：

  N-[4-[[6-[4-(三氟甲基)苯基]-4-嘧啶基]氧基]-2-苯并噻唑基]乙酰胺 、 碘甲烷 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 以63%的产率得到N-methyl-N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  2. Structure−Activity Relationships of 4-Oxopyrimidines Leading to the Selection of a Clinical Candidate

  摘要：

  A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.

  DOI：

  10.1021/jm070190p
• 作为产物：
  描述：

  4-氯-6-(4-(三氟甲基)苯基)嘧啶 在 potassium carbonate 作用下， 反应 8.0h， 生成 N-[4-[[6-[4-(三氟甲基)苯基]-4-嘧啶基]氧基]-2-苯并噻唑基]乙酰胺
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  2. Structure−Activity Relationships of 4-Oxopyrimidines Leading to the Selection of a Clinical Candidate

  摘要：

  A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.

  DOI：

  10.1021/jm070190p

文献信息

• [EN] CYSTATHIONINE-Y-GAMMA-LYASE (CSE) INHIBITORS<br/>[FR] INHIBITEURS DE LA CYSTATHIONINE-Y-GAMMA-LYASE (CSE)
  申请人：SOVA PHARMACEUTICALS INC

  公开号：WO2014018569A1

  公开（公告）日：2014-01-30

  Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit cystathionine-γ- lyase (CSE). Also described herein are methods for using such CSE inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from CSE inhibition.

  本文描述了抑制半胱氨酸-γ-裂解酶（CSE）的化合物和含有这些化合物的药物组合物。本文还描述了使用这些CSE抑制剂的方法，单独或与其他化合物结合，用于治疗需要CSE抑制的疾病或症状。
• TRPV1 Antagonists
  申请人：AbbVie Inc.

  公开号：US20130158067A1

  公开（公告）日：2013-06-20

  Disclosed herein are compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein X 1 , L, R x , R y , R z , A, m, n, p, q, s, and positions a and b are as defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

  披露于此的是公式（I）的化合物： 或其药用可接受的盐，其中X 1 ，L，R x ，R y ，R z ，A，m，n，p，q，s，以及位置a和b如说明书所述定义。还披露了包含此类化合物的组合物以及使用此类化合物和组合物治疗状况和失调的方法。
• [EN] CYSTATHIONINE-Upsilon-LYASE (CSE) INHIBITORS<br/>[FR] INHIBITEURS DE LA CYSTATHIONINE- Gamma -LYASE (CSE)
  申请人：SOVA PHARMACEUTICALS INC

  公开号：WO2014018570A1

  公开（公告）日：2014-01-30

  Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit cystathionine -γ-lyase (CSE). Also described herein are methods for using such CSE inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from CSE inhibition.

  本文描述了一些化合物和含有这些化合物的药物组合物，这些化合物抑制半胱氨酸-γ-裂解酶（CSE）。本文还描述了使用这些CSE抑制剂的方法，单独或与其他化合物结合，用于治疗需要CSE抑制的疾病或病况。
• [EN] VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS<br/>[FR] LIGANDS DE RECEPTEUR VANILLOIDE ET LEUR UTILISATION DANS DES TRAITEMENTS
  申请人：AMGEN INC

  公开号：WO2004014871A1

  公开（公告）日：2004-02-19

  Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

  含有通用结构和组成的化合物及其组合物，用于治疗急性、炎症性和神经痛、牙痛、普通头痛、偏头痛、集群性头痛、混合性血管和非血管综合症、紧张性头痛、普通炎症、关节炎、风湿性疾病、骨关节炎、炎症性肠病、炎症性眼病、炎症性或不稳定的膀胱疾病、牛皮癣、带有炎症成分的皮肤病、慢性炎症状况、炎症性疼痛及相关的高敏性和触痛，神经痛及相关的高敏性和触痛、糖尿病神经病疼痛、烧伤后神经痛、交感神经维持的疼痛、去神经症候群、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸道、泌尿生殖系统、胃肠道或血管区域的内脏运动障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、普通胃肠疾病、胃溃疡、十二指肠溃疡、腹泻、坏死性剂引起的胃病变、毛发生长、血管运动或过敏性鼻炎、支气管疾病或膀胱疾病。
• Vanilloid receptor ligands and their use in treatments
  申请人：——

  公开号：US20040082780A1

  公开（公告）日：2004-04-29

  Compounds having the general structure 1 and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

  具有一般结构1的化合物及其组成物，用于治疗急性、炎症和神经痛、牙痛、普通头痛、偏头痛、集群头痛、混合血管和非血管综合症、紧张性头痛、普通炎症、关节炎、风湿性疾病、骨关节炎、炎症性肠病、炎症性眼疾、炎症性或不稳定的膀胱疾病、牛皮癣、具有炎症成分的皮肤病、慢性炎症状况、炎症性疼痛及相关的高敏感性和触痛、神经痛及相关的高敏感性和触痛、糖尿病神经病痛、烧灼性疼痛、交感神经维持性疼痛、去神经症候群、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸、泌尿、胃肠或血管区域的内脏运动障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、普通胃肠障碍、胃溃疡、十二指肠溃疡、腹泻、坏死剂诱导的胃病变、毛发生长、血管运动或过敏性鼻炎、支气管疾病或膀胱疾病。