4-bromo-N-(2-fluorophenyl)-3-oxobutanamide | 953070-56-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-bromo-N-(2-fluorophenyl)-3-oxobutanamide
• CAS: 953070-56-9
• 化学式: C₁₀H₉BrFNO₂
• 分子量: 274.089
• InChiKey: KSQGYZZIZQXFPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-bromo-N-(2-fluorophenyl)-3-oxobutanamide 在 硫酸 作用下， 反应 18.0h， 以65%的产率得到4-(溴甲基)-8-氟-1H-喹啉-2-酮
  参考文献：
  名称：

  Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors that are Orally Active in Rodent Pain Models

  摘要：

  There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, mote recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42-potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.

  DOI：

  10.1021/jm900173b
• 作为产物：
  描述：

  N-(2-氟苯基)-3-氧代丁酰胺 在 溴 、 溶剂黄146 作用下， 反应 5.0h， 以68%的产率得到4-bromo-N-(2-fluorophenyl)-3-oxobutanamide
  参考文献：
  名称：

  QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS

  摘要：

  本发明涉及抑制诱导型NOS合酶的新奎诺酮化合物（化学式I），以及合成和使用这些化合物的方法，包括通过向患者施用这些化合物来治疗疾病的抑制或调节一氧化氮合成和/或降低一氧化氮水平的方法。

  公开号：

  US20080139558A1

文献信息

• QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
  申请人：Smith Nicholas D.

  公开号：US20080139558A1

  公开（公告）日：2008-06-12

  The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.

  本发明涉及抑制诱导型NOS合酶的新奎诺酮化合物（化学式I），以及合成和使用这些化合物的方法，包括通过向患者施用这些化合物来治疗疾病的抑制或调节一氧化氮合成和/或降低一氧化氮水平的方法。
• Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors that are Orally Active in Rodent Pain Models
  作者：Céline Bonnefous、Joseph E. Payne、Jeffrey Roppe、Hui Zhuang、Xiaohong Chen、Kent T. Symons、Phan M. Nguyen、Marciano Sablad、Natasha Rozenkrants、Yan Zhang、Li Wang、Daniel Severance、John P. Walsh、Nahid Yazdani、Andrew K. Shiau、Stewart A. Noble、Peter Rix、Tadimeti S. Rao、Christian A. Hassig、Nicholas D. Smith

  DOI：10.1021/jm900173b

  日期：2009.5.14

  There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, mote recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42-potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.
• [EN] QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS<br/>[FR] QUINOLONES UTILES EN TANT QU'INHIBITEURS DE L'OXYDE NITRIQUE SYNTHASE INDUCTIBLE
  申请人：KALYPSYS INC

  公开号：WO2007117778A9

  公开（公告）日：2009-05-22
• 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.