methyl imidazo[1,2-a]pyrazine-6-carboxylate | 1448536-57-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl imidazo[1,2-a]pyrazine-6-carboxylate
• 英文别名: Methyl imidazo[1,2-A]pyrazine-6-carboxylate
• CAS: 1448536-57-9
• 化学式: C₈H₇N₃O₂
• 分子量: 177.162
• InChiKey: KYTFUQMKAMGGQM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  56.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl imidazo[1,2-a]pyrazine-6-carboxylate 、 (4-(苯基磺酰基)苯基)甲胺 在 三甲基铝 作用下， 以 甲苯 为溶剂， 反应 4.67h， 以28%的产率得到N-{[4-(benzenesulfonyl)phenyl]methyl}imidazo[1,2-a]pyrazine-6-carboxamide
  参考文献：
  名称：

  Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

  摘要：

  Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MOCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

  DOI：

  10.1021/jm4008664
• 作为产物：
  描述：

  2-溴吡嗪[4,5-a]并吡咯 在 盐酸 、 四(三苯基膦)钯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 14.25h， 生成 methyl imidazo[1,2-a]pyrazine-6-carboxylate
  参考文献：
  名称：

  Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

  摘要：

  Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MOCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

  DOI：

  10.1021/jm4008664

文献信息

• ANTI-ALS COMPOUNDS
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US20230037538A1

  公开（公告）日：2023-02-09

  The present invention relates to compounds expected to be useful in the prevention and/or treatment of diseases such as amyotrophic lateral sclerosis, frontotemporal dementia, chronic traumatic encephalopathy, Alzheimer's disease, frontotemporal lobar degeneration, multisystem proteinopathy and the like, a method for preventing or treating such diseases, and the like.
• Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
  作者：Xiaozhang Zheng、Paul Bauer、Timm Baumeister、Alexandre J. Buckmelter、Maureen Caligiuri、Karl H. Clodfelter、Bingsong Han、Yen-Ching Ho、Nikolai Kley、Jian Lin、Dominic J. Reynolds、Geeta Sharma、Chase C. Smith、Zhongguo Wang、Peter S. Dragovich、Janet Gunzner-Toste、Bianca M. Liederer、Justin Ly、Thomas O’Brien、Angela Oh、Leslie Wang、Weiru Wang、Yang Xiao、Mark Zak、Guiling Zhao、Po-wai Yuen、Kenneth W. Bair

  DOI：10.1021/jm4008664

  日期：2013.8.22

  Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MOCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.