| 626238-57-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• CAS: 626238-57-1
• 化学式: C₂₂H₃₁ClN₄O₂
• 分子量: 418.967
• InChiKey: NXSFKUCSWRJBEE-HZCBDIJESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.87
• 重原子数：
  29.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  72.46
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  ethyl (1r,4r)-4-hydroxy-1,4-dimethylcyclohexane-1-carboxylate 、 在 2-(三甲基硅烷基)乙氧甲基氯 、 sodium hydride 、 2,2,6,6-tetramethylpiperidinyl-lithium 、 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists

  摘要：

  The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.04.023

文献信息

• 2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists
  作者：Kensuke Kobayashi、Minaho Uchiyama、Hirobumi Takahashi、Hiroshi Kawamoto、Satoru Ito、Takashi Yoshizumi、Hiroshi Nakashima、Tetsuya Kato、Atsushi Shimizu、Izumi Yamamoto、Masanori Asai、Hiroshi Miyazoe、Akio Ohno、Mioko Hirayama、Satoshi Ozaki、Takeshi Tani、Yasuyuki Ishii、Takeshi Tanaka、Takanobu Mochidome、Kiyoshi Tadano、Takahiro Fukuroda、Hisashi Ohta、Osamu Okamoto

  DOI：10.1016/j.bmcl.2009.04.023

  日期：2009.6

  The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist. (C) 2009 Elsevier Ltd. All rights reserved.