N-{[4-(benzenesulfonyl)phenyl]methyl}-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide | 1448536-36-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: N-{[4-(benzenesulfonyl)phenyl]methyl}-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
• 英文别名: N-[[4-(benzenesulfonyl)phenyl]methyl]-1-methylpyrrolo[2,3-c]pyridine-2-carboxamide
• CAS: 1448536-36-4
• 化学式: C₂₂H₁₉N₃O₃S
• 分子量: 405.477
• InChiKey: ASNWVMQWFPQWOT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  89.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid 、 (4-(苯基磺酰基)苯基)甲胺 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以4%的产率得到N-{[4-(benzenesulfonyl)phenyl]methyl}-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-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

文献信息

• 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.