{2-[({(8S,11R,12S)-12-[(hydroxyamino)carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecan-8-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetic acid | 215938-59-3

• 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: {2-[({(8S,11R,12S)-12-[(hydroxyamino)carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecan-8-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetic acid
• 英文别名: 2-[2-[[(8S,11R,12S)-12-(hydroxycarbamoyl)-11-(2-methylpropyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid
• CAS: 215938-59-3
• 化学式: C₂₃H₃₅N₅O₈S
• 分子量: 541.626
• InChiKey: MLSZZVIWIDSFOK-BBWFWOEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  224
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  吗啉 、 {2-[({(8S,11R,12S)-12-[(hydroxyamino)carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecan-8-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetic acid 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 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 2.0h， 以35 mg的产率得到(8S,11R,12S)-11-Isobutyl-2,10-dioxo-1-oxa-3,9-diaza-cyclopentadecane-8,12-dicarboxylic acid 12-hydroxyamide 8-{[4-(2-morpholin-4-yl-2-oxo-ethyl)-thiazol-2-yl]-amide}
  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：

  4-benzyl 1-tert-butyl (2S,3R)-2-allyl-3-isobutylbutanedioate 在 palladium on activated charcoal N-甲基吗啉 、 lithium hydroxide 、 9-borabicyclo[3.3.1]nonane dimer 、 盐酸羟胺 、 氢气 、 potassium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.33h， 生成 {2-[({(8S,11R,12S)-12-[(hydroxyamino)carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecan-8-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetic acid
  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