N2-(4-bromo-2-((4-chloro-2-methoxy-6-methylphenyl)amino)-1-methyl-1H-benzimidazol-7-yl)-N2-ethylglycinamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N2-(4-bromo-2-((4-chloro-2-methoxy-6-methylphenyl)amino)-1-methyl-1H-benzimidazol-7-yl)-N2-ethylglycinamide
• 英文别名: 2-[[7-Bromo-2-(4-chloro-2-methoxy-6-methylanilino)-3-methylbenzimidazol-4-yl]-ethylamino]acetamide；2-[[7-bromo-2-(4-chloro-2-methoxy-6-methylanilino)-3-methylbenzimidazol-4-yl]-ethylamino]acetamide
• 化学式: C₂₀H₂₃BrClN₅O₂
• 分子量: 480.792
• InChiKey: NFKQSYYYHBCOLL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  85.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 在 N-甲基吡咯烷酮 、 N-溴代丁二酰亚胺(NBS) 、 1-羟基-1H-苯并三唑铵盐 、 sodium cyanoborohydride 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 134.0h， 生成 N2-(4-bromo-2-((4-chloro-2-methoxy-6-methylphenyl)amino)-1-methyl-1H-benzimidazol-7-yl)-N2-ethylglycinamide
  参考文献：
  名称：

  Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

  摘要：

  Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 mu L/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering win vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 mu L/min/mg) than compound 1. Compound 24d demonstrated potent CRF1 binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CREI receptor. Orally administered compound 24d (6-24 mu mol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.11.011

文献信息

• Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist
  作者：Michiyo Mochizuki、Takuto Kojima、Katsumi Kobayashi、Etsuo Kotani、Yuji Ishichi、Naoyuki Kanzaki、Hideyuki Nakagawa、Teruaki Okuda、Yohei Kosugi、Takahiko Yano、Yuu Sako、Maiko Tanaka、Kazuyoshi Aso

  DOI：10.1016/j.bmc.2016.11.011

  日期：2017.3

  Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 mu L/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering win vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 mu L/min/mg) than compound 1. Compound 24d demonstrated potent CRF1 binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CREI receptor. Orally administered compound 24d (6-24 mu mol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d. (C) 2016 Elsevier Ltd. All rights reserved.