[(1R)-1-phenylethyl] N-[5-(4-bromophenyl)-1-methyltriazol-4-yl]carbamate | 1423707-24-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [(1R)-1-phenylethyl] N-[5-(4-bromophenyl)-1-methyltriazol-4-yl]carbamate
• CAS: 1423707-24-7
• 化学式: C₁₈H₁₇BrN₄O₂
• 分子量: 401.263
• InChiKey: UXQBDCLWSXCZBR-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  69
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [(1R)-1-phenylethyl] N-[5-(4-bromophenyl)-1-methyltriazol-4-yl]carbamate 、 甲基4-(1-乙氧基羰基环丙基)苯硼酸频哪醇酯 在 potassium phosphate 、 palladium diacetate 、 lithium hydroxide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 15.0h， 生成 1-{4'-[3-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-3H-[1,2,3]triazol-4-yl]biphenyl-4-yl}cyclopropanecarboxylic acid
  参考文献：
  名称：

  Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts

  摘要：

  Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.

  DOI：

  10.1021/jm301022v
• 作为产物：
  描述：

  5-(4-bromo-phenyl)-1-trimethylsilanylmethyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester 在 叠氮磷酸二苯酯 、 四丁基氟化铵 、 水 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 5.17h， 生成 [(1R)-1-phenylethyl] N-[5-(4-bromophenyl)-1-methyltriazol-4-yl]carbamate
  参考文献：
  名称：

  Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts

  摘要：

  Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.

  DOI：

  10.1021/jm301022v

文献信息

• [EN] LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DES RÉCEPTEURS D'ACIDE LYSOPHOSPHATIDIQUE
  申请人：INTERMUNE INC

  公开号：WO2013025733A1

  公开（公告）日：2013-02-21

  Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with one or more of the lysophosphatidic acid receptors are provided.

  提供了化合物、制备这种化合物的方法、包含这种化合物的药物组合物和药物，以及使用这种化合物治疗、预防或诊断与一种或多种赖氨酸磷脂酸受体相关的疾病、紊乱或状况的方法。
• LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS
  申请人：Buckman Brad O.

  公开号：US20130072449A1

  公开（公告）日：2013-03-21

  Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with one or more of the lysophosphatidic acid receptors are provided.
• US8975235B2
  申请人：——

  公开号：US8975235B2

  公开（公告）日：2015-03-10
• Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts
  作者：Yimin Qian、Matthew Hamilton、Achyutharao Sidduri、Stephen Gabriel、Yonglin Ren、Ruoqi Peng、Rama Kondru、Arjun Narayanan、Terry Truitt、Rachid Hamid、Yun Chen、Lin Zhang、Adrian J. Fretland、Ruben Alvarez Sanchez、Kung-Ching Chang、Matthew Lucas、Ryan C. Schoenfeld、Dramane Laine、Maria E. Fuentes、Christopher S. Stevenson、David C. Budd

  DOI：10.1021/jm301022v

  日期：2012.9.13

  Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.