(3R,5S,8S)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylic acid | 957475-32-0

• 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: (3R,5S,8S)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylic acid
• 英文别名: (3R,5S,8S)-7-oxo-8-propan-2-yl-2-oxa-11-thia-6,9,24,27-tetrazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24),10(27),12,18(26),19,21(25),22-heptaene-5-carboxylic acid
• CAS: 957475-32-0
• 化学式: C₂₆H₃₀N₄O₄S
• 分子量: 494.615
• InChiKey: MGOIMDXKBCRKRX-HJNYFJLDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  35
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  129
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide 、 (3R,5S,8S)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylic acid 在 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 反应 12.0h， 以47 mg的产率得到(3R,5S,8S)-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylate
  参考文献：
  名称：

  Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

  摘要：

  Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and Cellular activity. Among these, Compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.

  DOI：

  10.1021/jm900524b
• 作为产物：
  描述：

  methyl (3R,5S,8S)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 2.0h， 生成 (3R,5S,8S)-8-isopropyl-7-oxo-2-oxa-11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.1(3,5).1(10,13).0(21,25)]octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxylic acid
  参考文献：
  名称：

  Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

  摘要：

  Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and Cellular activity. Among these, Compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.

  DOI：

  10.1021/jm900524b