12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid methyl ester | 367258-55-7

• 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: 12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid methyl ester
• 英文别名: methyl (7R,9S,12S)-12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]heneicosa-1(20),16,18-triene-9-carboxylate；methyl (7R,9S,12S)-12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylate
• CAS: 367258-55-7
• 化学式: C₂₅H₃₄N₂O₆
• 分子量: 458.555
• InChiKey: HFJBDZALCUTSER-GIWBLDEGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid methyl ester 在 N-甲基吗啉 、 lithium hydroxide 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (R,S)-((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
  参考文献：
  名称：

  Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles

  摘要：

  The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a number of P2 proline-based macrocyclic alpha-ketoamide inhibitors were prepared and investigated in an HCV NS3 serine protease continuous assay (K-i*). The biological activity varied substantially depending on factors such as the ring size, number of amino acid residues, number of methyl substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones (24, K-i* = 8 nM). The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compounds were equally potent, while fifteen-membered analogues were slightly less active. gem-Dimethyl substituents at the linker improved the potency of all inhibitors (the best compound was 45, Ki* = 6 nM). The combination of tert-leucine at P3 and dimethyl substituents at the linker in compound 47 realized a selectivity of 307 against human neutrophil elastase. Compound 45 had an IC50 of 130 nM in a cellular replicon assay, while IC50 for 24 was 400 nM. Several compounds had excellent subcutaneous AUC and bioavailability in rats. Although tripeptide compound 40 was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compounds 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 methyl group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (> 20-fold greater than that of 1) and in structural depeptization.

  DOI：

  10.1021/jm050820s
• 作为产物：
  描述：

  Boc-L-羟脯氨酸 在 10percent Pd/C N-甲基吗啉 、 盐酸 、 氢气 、 sodium hydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 、 三苯基膦 、 sodium iodide 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 112.0h， 生成 12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.1^7,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid methyl ester
  参考文献：
  名称：

  Novel Dipeptide Macrocycles from 4-Oxo, -Thio, and -Amino-Substituted Proline Derivatives

  摘要：

  Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy.

  DOI：

  10.1021/jo011160b

文献信息

• P2–P4 Macrocyclic inhibitors of hepatitis C virus NS3-4A serine protease
  作者：Ashok Arasappan、F. George Njoroge、Kevin X. Chen、Srikanth Venkatraman、Tejal N. Parekh、Haining Gu、John Pichardo、Nancy Butkiewicz、Andrew Prongay、Vincent Madison、Viyyoor Girijavallabhan

  DOI：10.1016/j.bmcl.2006.05.022

  日期：2006.8

  Synthesis and HCV NS3 serine protease inhibitory activity of 4-hydroxyproline derived macrocyclic inhibitors and SAR around this macrocyclic core is described in this communication. X-ray structure of inhibitor 38 bound to the protease is discussed.
• Novel Dipeptide Macrocycles from 4-Oxo, -Thio, and -Amino-Substituted Proline Derivatives
  作者：Ashok Arasappan、Kevin X. Chen、F. George Njoroge、Tejal N. Parekh、Viyyoor Girijavallabhan

  DOI：10.1021/jo011160b

  日期：2002.5.1

  Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy.
• Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles
  作者：Kevin X. Chen、F. George Njoroge、Ashok Arasappan、Srikanth Venkatraman、Bancha Vibulbhan、Weiying Yang、Tejal N. Parekh、John Pichardo、Andrew Prongay、Kuo-Chi Cheng、Nancy Butkiewicz、Nanhua Yao、Vincent Madison、Viyyoor Girijavallabhan

  DOI：10.1021/jm050820s

  日期：2006.2.1

  The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a number of P2 proline-based macrocyclic alpha-ketoamide inhibitors were prepared and investigated in an HCV NS3 serine protease continuous assay (K-i*). The biological activity varied substantially depending on factors such as the ring size, number of amino acid residues, number of methyl substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones (24, K-i* = 8 nM). The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compounds were equally potent, while fifteen-membered analogues were slightly less active. gem-Dimethyl substituents at the linker improved the potency of all inhibitors (the best compound was 45, Ki* = 6 nM). The combination of tert-leucine at P3 and dimethyl substituents at the linker in compound 47 realized a selectivity of 307 against human neutrophil elastase. Compound 45 had an IC50 of 130 nM in a cellular replicon assay, while IC50 for 24 was 400 nM. Several compounds had excellent subcutaneous AUC and bioavailability in rats. Although tripeptide compound 40 was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compounds 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 methyl group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (> 20-fold greater than that of 1) and in structural depeptization.