(9S,12R,13S)-12-Isobutyl-3,11-dioxo-1-oxa-4,10-diaza-cyclotridecane-9,13-dicarboxylic acid 13-(benzyloxy-amide) 9-methylamide | 356548-87-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (9S,12R,13S)-12-Isobutyl-3,11-dioxo-1-oxa-4,10-diaza-cyclotridecane-9,13-dicarboxylic acid 13-(benzyloxy-amide) 9-methylamide
• CAS: 356548-87-3
• 化学式: C₂₄H₃₆N₄O₆
• 分子量: 476.573
• InChiKey: BMWBTWHHQSYUSL-DYXWJJEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.81
• 重原子数：
  34.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  134.86
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (9S,12R,13S)-12-Isobutyl-3,11-dioxo-1-oxa-4,10-diaza-cyclotridecane-9,13-dicarboxylic acid 13-(benzyloxy-amide) 9-methylamide 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以62%的产率得到SC 903
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of Macrocyclic Hydroxamic Acids That Inhibit Tumor Necrosis Factor α Release in Vitro and in Vivo

  摘要：

  To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the PI and P2 ' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2 ' linkers. With an N-methylamide at P3 ', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3 ' -P4 ' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of less than or equal to 0.2 muM in whole blood assay (WBA). Although the P3 ' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3 ' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3 ', an N-methylamide at P4 ' provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 muM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4 ' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC50 = 0.067 muM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K-i values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

  DOI：

  10.1021/jm010127e
• 作为产物：
  描述：

  (2R)-2-[(1S)-2-butoxy-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]-2-oxoethyl]-4-methylpentanoic acid 在 palladium on activated charcoal 盐酸 、 lithium hydroxide 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 作用下， 以 1,4-二氧六环 为溶剂， 生成 (9S,12R,13S)-12-Isobutyl-3,11-dioxo-1-oxa-4,10-diaza-cyclotridecane-9,13-dicarboxylic acid 13-(benzyloxy-amide) 9-methylamide
  参考文献：
  名称：

  基质金属蛋白酶和TNF-α产生的环状抑制剂的设计与合成。

  摘要：

  DOI：

  10.1021/jm970849z