methyl (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.1(4,7).1(17,20).0(6,11)]nonacosa-6,8,10,12,17,20(28)-hexaene-25-carboxylate | 1196684-14-6

• 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: methyl (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.1(4,7).1(17,20).0(6,11)]nonacosa-6,8,10,12,17,20(28)-hexaene-25-carboxylate
• 英文别名: methyl (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetrazapentacyclo[22.2.1.14,7.117,20.06,11]nonacosa-6,8,10,12,17,20(28)-hexaene-25-carboxylate
• CAS: 1196684-14-6
• 化学式: C₂₉H₃₆N₄O₅S
• 分子量: 552.695
• InChiKey: STZJDILVUXJLPF-VWBVCBQBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  39
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  126
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.1(4,7).1(17,20).0(6,11)]nonacosa-6,8,10,12,17,20(28)-hexaene-25-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 2.0h， 生成 (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetrazapentacyclo[22.2.1.14,7.117,20.06,11]nonacosa-6,8,10,12,17,20(28)-hexaene-25-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
• 作为产物：
  描述：

  methyl N-[4-(4-pentenyl)-1,3-thiazol-2-lyl]-3-methyl-L-valyl-(4R)-4-{[(4-ethenyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate 在 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 2.0h， 以82 mg的产率得到methyl (1R,12E,22S,25S)-22-tert-butyl-3,23-dioxo-2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.1(4,7).1(17,20).0(6,11)]nonacosa-6,8,10,12,17,20(28)-hexaene-25-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

文献信息

• Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement
  作者：M. Emilia Di Francesco、Gabriella Dessole、Emanuela Nizi、Paola Pace、Uwe Koch、Fabrizio Fiore、Silvia Pesci、Jillian Di Muzio、Edith Monteagudo、Michael Rowley、Vincenzo Summa

  DOI：10.1021/jm900524b

  日期：2009.11.26

  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.