(4-((1-Propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)methanamine | 1450723-60-0

• 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-((1-Propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)methanamine
• 英文别名: [4-(1-propylpyrazol-4-yl)sulfonylphenyl]methanamine
• CAS: 1450723-60-0
• 化学式: C₁₃H₁₇N₃O₂S
• 分子量: 279.363
• InChiKey: JYIKZOHUNYBSMY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.58
• 重原子数：
  19.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  77.98
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (4-((1-Propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)methanamine 以 乙醇 、 甲苯 为溶剂， 反应 4.0h， 生成 N-[[4-(1-propylpyrazol-4-yl)sulfonylphenyl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide
  参考文献：
  名称：

  Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

  摘要：

  Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.06.090
• 作为产物：
  描述：

  sodium 4-(acetamidomethyl)benzenesulfinate 在 盐酸 、 水 、 copper diacetate 作用下， 以 二甲基亚砜 、 异丙醇 为溶剂， 反应 16.0h， 生成 (4-((1-Propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)methanamine
  参考文献：
  名称：

  Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

  摘要：

  Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.08.074

文献信息

• Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility
  作者：Mark Zak、Bianca M. Liederer、Deepak Sampath、Po-wai Yuen、Kenneth W. Bair、Timm Baumeister、Alexandre J. Buckmelter、Karl H. Clodfelter、Eric Cheng、Lisa Crocker、Bang Fu、Bingsong Han、Guangkun Li、Yen-Ching Ho、Jian Lin、Xiongcai Liu、Justin Ly、Thomas O’Brien、Dominic J. Reynolds、Nicholas Skelton、Chase C. Smith、Suzanne Tay、Weiru Wang、Zhongguo Wang、Yang Xiao、Lei Zhang、Guiling Zhao、Xiaozhang Zheng、Peter S. Dragovich

  DOI：10.1016/j.bmcl.2014.12.026

  日期：2015.2

  Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD(7.4) was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies. (C) 2014 Elsevier Ltd. All rights reserved.