(R)-2-[7-(3,5-Dimethoxy-benzylamino)-1,1-dioxo-1,3,4,5-tetrahydro-1λ6-benzo[f][1,2,5]thiadiazepin-2-yl]-4-methyl-pentanoic acid benzyloxy-amide | 529496-47-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-2-[7-(3,5-Dimethoxy-benzylamino)-1,1-dioxo-1,3,4,5-tetrahydro-1λ6-benzo[f][1,2,5]thiadiazepin-2-yl]-4-methyl-pentanoic acid benzyloxy-amide
• CAS: 529496-47-7
• 化学式: C₃₀H₃₈N₄O₆S
• 分子量: 582.721
• InChiKey: PCJLCMIYNYAARD-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.39
• 重原子数：
  41.0
• 可旋转键数：
  12.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  118.23
• 氢给体数：
  3.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (R)-2-[7-(3,5-Dimethoxy-benzylamino)-1,1-dioxo-1,3,4,5-tetrahydro-1λ6-benzo[f][1,2,5]thiadiazepin-2-yl]-4-methyl-pentanoic acid benzyloxy-amide 在 Pd-BaSO₄ 氢气 作用下， 以 甲醇 为溶剂， 反应 0.45h， 以27%的产率得到(2R)-2-[7-[(3,5-dimethoxyphenyl)methylamino]-1,1-dioxo-4,5-dihydro-3H-1lambda6,2,5-benzothiadiazepin-2-yl]-N-hydroxy-4-methylpentanamide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Benzothiadiazepine Hydroxamates as Selective Tumor Necrosis Factor-α Converting Enzyme Inhibitors

  摘要：

  Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K-i = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC50 = 0.35 muM), while compound 62 was the most active in the WBA (IC50 = 1.4 muM).

  DOI：

  10.1021/jm020475w
• 作为产物：
  描述：

  tert-butyl (2R)-2-(7-amino-1,1-dioxo-4,5-dihydro-3H-1lambda6,2,5-benzothiadiazepin-2-yl)-4-methylpentanoate 在 sodium tetrahydroborate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 (R)-2-[7-(3,5-Dimethoxy-benzylamino)-1,1-dioxo-1,3,4,5-tetrahydro-1λ6-benzo[f][1,2,5]thiadiazepin-2-yl]-4-methyl-pentanoic acid benzyloxy-amide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Benzothiadiazepine Hydroxamates as Selective Tumor Necrosis Factor-α Converting Enzyme Inhibitors

  摘要：

  Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K-i = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC50 = 0.35 muM), while compound 62 was the most active in the WBA (IC50 = 1.4 muM).

  DOI：

  10.1021/jm020475w