1350514-68-9

• 常用中文名：格拉瑞韦
• 常用英文名：MK-5172
• CAS号：1350514-68-9
• 分子式：C₃₈H₅₀N₆O₉S
• 分子量：766.903
• 相关类别： 信号通路 抗感染 HCV
• 发布时间：2018-05-11 08:00:00
• 更新时间：2024-01-02 17:44:14
• Grazoprevir (MK-5172) 是选择性的丙型肝炎病毒 NS3/4a蛋白酶抑制剂,作用于 gt1b,gt1a,gt2a,gt2b 和 gt3a的 Ki 分别为 0.01 nM,0.01 nM,0.08 nM,0.15 nM 和 0.90 nM。

名称

• 中文名: 格拉瑞韦
• 英文名: Grazoprevir
• 中文别名: 格佐普韦
• 英文别名: (1R,18R,20R,24S,27S)-N-{(1R,2S)-1-[(Cyclopropylsulfonyl)carbamoyl]-2-vinylcyclopropyl}-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.0.0.0]nonacosa-3,5,7,9,11-pentaene-27-carboxamide; UNII-8YE81R1X1J; 8H-7,10-Methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-ethenylcyclopropyl]-5-(1,1-dimethylethyl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-, (1aR,5S,8S,10R,22aR)-; (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide; MK-5172; CS-1374; grazoprevir; MK5172

物化性质

• 密度: 1.4±0.1 g/cm3
• 分子式: C₃₈H₅₀N₆O₉S
• 分子量: 766.903
• 精确质量: 766.335999
• PSA: 203.60000
• LogP: 3.93
• 外观性状: 粉末
• 折射率: 1.633
• 储存条件: -20℃

生物活性

• 描述: Grazoprevir (MK-5172) 是选择性的丙型肝炎病毒 NS3/4a蛋白酶抑制剂,作用于 gt1b,gt1a,gt2a,gt2b 和 gt3a的 Ki 分别为 0.01 nM,0.01 nM,0.08 nM,0.15 nM 和 0.90 nM。
• 相关类别:
  信号通路 >> 代谢酶/蛋白酶 >> HCV蛋白酶
  信号通路 >> 抗感染 >> HCV
  研究领域 >> 感染
• 靶点:

  Ki: 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a)[1]

• 体外研究: 在生物化学分析中,Grazoprevir(MK-5172)对一组主要基因型和具有常见抗性突变的变体有效,Ki为0.01±<0.01 nM(gt1b),0.01±0.01 nM(gt1a),0.08±0.02 nM (gt2a),0.15±0.06nM(gt2b),0.90±0.2nM(gt3a),0.07±0.01nM(gt1bR155K),0.14±0.03nM(gt1bD168V),0.30±0.04nM(gt1bD168Y),5.3±0.9nM(gt1bA156T)分别为12±2nM(gt1bA156V)。在复制子测定中,Grazoprevir显示针对基因型1a,1b和2a的亚纳摩尔至低纳摩尔EC50,对于gt1bcon1,gt1a和gt2a,EC50分别为0.5±0.1nM,2±1nM和2±1nM。 Grazoprevir对一组HCV复制突变体NS5A(Y93H)(EC50 = 0.7±0.3 nM),NS5B核苷(S282T)(EC50 = 0.3±0.1 nM)和NS5B(C316Y)(EC50 = 0.4±0.2)有效[ 1]。 Grazoprevir(MK-5172)保持对gt 3a酶以及广泛的突变酶组的优异效力,在复制子系统中具有优异的效力[gt1b IC50(50％NHS)= 7.4nM; gtaa IC50(40％NHS)= 7 nM],显示出优异的大鼠肝脏暴露[2]。
• 体内研究: Grazoprevir(MK-5172)在体内对慢性HCV感染的黑猩猩有效[1]。当给予狗时,Grazoprevir(MK-5172)显示静脉给药后5 mL/min/kg的低清除率和3 h的半衰期,并且在1 mg/kg口服后具有良好的血浆暴露(AUC =0.4μMh)剂量。狗肝脏活检研究表明,1 mg/kg口服剂量后Grazoprevir的肝脏浓度在24 h时间点为1.4μM。与其在大鼠中的行为类似,Grazoprevir证明有效分配到肝脏组织中,并且相对于效力,在狗口服给药后24小时维持高肝脏浓度[2]。
• 动物实验: 大鼠和狗[1]在大鼠和狗中进行研究。对于格拉霉素静脉内给予大鼠或狗的研究，将化合物配制在聚乙二醇200（PEG200）中，并以2mg / kg体重（大鼠）或0.5mg / kg（狗）的推注给药。对于口服研究，化合物的结晶钾盐以5mg / kg（大鼠）或1mg / kg（狗）的PEG400溶液给药。对于所有研究，在适当的时间将血液样品收集在含EDTA的管中，并通过离心分离血浆并储存在-70℃直至分析。 Grazoprevir（MK-5172）水平的定量通过蛋白质沉淀后的高效液相色谱/质谱（LC / MS / MS）进行。在实验结束时从大鼠研究中获得肝样品。对于狗，在镇静后收集肝脏活组织检查样品（20μL）。将组织样品在四体积的去离子水中匀浆，并在蛋白质沉淀后通过LC / MS / MS测定药物浓度。
• 参考文献:

  [1]. Summa V, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7.

  [2]. Harper S, et al. Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6.

合成路线

1206524-84-6 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

1361028-94-5 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

1206524-83-5 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

59548-39-9 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

63038-27-7 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

31910-18-6 ~% 1350514-68-9

文献：Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; Romano, Joseph J.; Bush, Kimberly J.; Gilbert, Kevin F.; McIntyre, Charles J.; Nguyen, Kevin T.; Nizi, Emanuela; Carroll, Steven S.; Ludmerer, Steven W.; Burlein, Christine; Dimuzio, Jillian M.; Graham, Donald J.; McHale, Carolyn M.; Stahlhut, Mark W.; Olsen, David B.; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M.; Rowley, Michael; Coleman, Paul J.; Vacca, Joseph P.; Summa, Vincenzo; Liverton, Nigel J. ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 4 p. 332 - 336

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