6-oxo-4-thiophen-2-yl-2-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)benzylsulfanyl]-1,6-dihydropyrimidine-5-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-oxo-4-thiophen-2-yl-2-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)benzylsulfanyl]-1,6-dihydropyrimidine-5-carbonitrile
• 英文别名: 6-oxo-4-thiophen-2-yl-2-[[3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methylsulfanyl]-1H-pyrimidine-5-carbonitrile
• 化学式: C₁₉H₁₀F₃N₅O₂S₂
• 分子量: 461.448
• InChiKey: VBXYAZJAXSQVEB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  158
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  间甲基苯腈 在 吡啶 、 N-溴代丁二酰亚胺(NBS) 、 盐酸羟胺 、 碳酸氢钠 、 potassium carbonate 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 7.0h， 生成 6-oxo-4-thiophen-2-yl-2-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)benzylsulfanyl]-1,6-dihydropyrimidine-5-carbonitrile
  参考文献：
  名称：

  α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD⁺) Biosynthesis

  摘要：

  NAD(+) has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD(+) homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD(+) on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of 4 novo NAD(+) biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thieny1)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0.013 mu M) that increases NAD(+) levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD(+) biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAV-supply or homeostasis.

  DOI：

  10.1021/acs.jmedchem.7b01254