N-[3-cyano-4-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide | 925930-16-1

• 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
• 英文名称: N-[3-cyano-4-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide
• 英文别名: N-[3-Cyano-4-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide；N-[3-cyano-4-[3-[2-(dimethylamino)ethyl-methylamino]phenyl]-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide
• CAS: 925930-16-1
• 化学式: C₂₈H₂₆FN₅O₃
• 分子量: 499.545
• InChiKey: UYGVYXOUEMQEKH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  聚合甲醛 、 N-[4-{3-[(2-aminoethyl)amino]phenyl}-3-cyano-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide dihydrochloride 在 sodium cyanoborohydride 、 溶剂黄146 、 碳酸氢钠 作用下， 以 甲醇 、 水 为溶剂， 反应 72.0h， 以77%的产率得到N-[3-cyano-4-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-6-(4-fluoro-2-hydroxyphenyl)pyridin-2-yl]furan-2-carboxamide
  参考文献：
  名称：

  2-Acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats

  摘要：

  GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.05.061

文献信息

• PYRIDYLPHENOL COMPOUND AND USE THEREOF
  申请人：Sasaki Satoshi

  公开号：US20090156646A1

  公开（公告）日：2009-06-18

  The present invention provides a compound which has metastin receptor antagonist activity and is useful for preventing and treating hormone-dependent cancer, benign prostatomegaly, endometriosis, precocious puberty, uterine myoma or the like. More specifically, the present invention provides a compound, represented by the formula: or a salt thereof, a prodrug thereof, and a pharmaceutical agent containing the same; wherein Ring A represents a 5- to 8-membered homocyclic or heterocyclic group optionally having a substituent other than formula —X-R 1 wherein X represents a bond or a spacer, and R 1 represents optionally substituted amino or an optionally substituted nitrogen-containing heterocyclic group; Ring B represents an optionally substituted benzene ring; R 2 represents an optionally substituted homocyclic or heterocyclic group; and R 3 and R 4 independently represent a hydrogen atom, cyano, acyl or an optionally substituted hydrocarbon group.

  本发明提供了一种具有转移素受体拮抗活性的化合物，可用于预防和治疗激素依赖性癌症、良性前列腺增生、子宫内膜异位症、早熟、子宫肌瘤等。更具体地，本发明提供了一种化合物，其表示为以下公式：或其盐、前药及含有该化合物的药物制剂；其中环A表示一个5-至8-成员的同环或异环族群，可选地具有除公式—X-R1以外的取代基，其中X表示键或空间组分，而R1表示可选地取代的氨基或可选地取代的含氮杂环族群；环B表示可选地取代的苯环；R2表示可选地取代的同环或异环族群；而R3和R4独立地表示氢原子、氰基、酰基或可选地取代的碳氢基团。
• 2-Acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats
  作者：Toshitake Kobayashi、Satoshi Sasaki、Naoki Tomita、Seiji Fukui、Masaharu Nakayama、Atsushi Kiba、Masami Kusaka、Shin-ichi Matsumoto、Masashi Yamaguchi、Fumio Itoh、Atsuo Baba

  DOI：10.1016/j.bmc.2010.05.061

  日期：2010.7

  GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases. (C) 2010 Elsevier Ltd. All rights reserved.