2-(cyclobutylmethyl)-1H-benzo[d]imidazole | 882774-52-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-(cyclobutylmethyl)-1H-benzo[d]imidazole
• 英文别名: 2-(cyclobutylmethyl)-1H-benzimidazole
• CAS: 882774-52-9
• 化学式: C₁₂H₁₄N₂
• 分子量: 186.257
• InChiKey: MSLVRYQKGGCBJY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  28.7
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  环丁基乙酸 、 邻苯二胺 在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 4.0h， 以31%的产率得到2-(cyclobutylmethyl)-1H-benzo[d]imidazole
  参考文献：
  名称：

  Discovery of Dual Inducible/Neuronal Nitric Oxide Synthase (iNOS/nNOS) Inhibitor Development Candidate 4-((2-Cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) Part 2: Identification of a Novel, Potent, and Selective Series of Benzimidazole-Quinolinone iNOS/nNOS Dimerization Inhibitors That Are Orally Active in Pain Models

  摘要：

  Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047-3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses or 1000 mg/kg, demonstrating a wide therapeutic margin.

  DOI：

  10.1021/jm100828n

文献信息

• Discovery of Dual Inducible/Neuronal Nitric Oxide Synthase (iNOS/nNOS) Inhibitor Development Candidate 4-((2-Cyclobutyl-1<i>H</i>-imidazo[4,5-<i>b</i>]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1<i>H</i>)-one (KD7332) Part 2: Identification of a Novel, Potent, and Selective Series of Benzimidazole-Quinolinone iNOS/nNOS Dimerization Inhibitors That Are Orally Active in Pain Models
  作者：Joseph E. Payne、Céline Bonnefous、Kent T. Symons、Phan M. Nguyen、Marciano Sablad、Natasha Rozenkrants、Yan Zhang、Li Wang、Nahid Yazdani、Andrew K. Shiau、Stewart A. Noble、Peter Rix、Tadimeti S. Rao、Christian A. Hassig、Nicholas D. Smith

  DOI：10.1021/jm100828n

  日期：2010.11.11

  Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047-3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses or 1000 mg/kg, demonstrating a wide therapeutic margin.