Danoprevir (ITMN-191) 是一种具有口服活

Danoprevir  (Synonyms: 丹诺普韦; ITMN-191; R7227; RO5190591; RG7227)

Danoprevir (ITMN-191) 是一种具有口服活性的 NS3/4A蛋白酶抑制剂，IC₅₀ 值为 0.29 nM。与其他 53 种蛋白酶 (IC₅₀高于 10 μM) 相比，对 NS3/4A 具有高选择性。Danoprevir (ITMN-191) 抑制 HCV 基因型 1a, 1b, 4, 5, 6 (IC₅₀s=0.2-0.4 nM) 和 2b, 3a (IC₅₀s=1.6, 3.5 nM)。Danoprevir 也是 SARS-CoV 3CL^pro 的抑制剂，IC₅₀ 为 0.05 μM。

美国medchemexpress（MCE)浙江省一级代理:杭州昊鑫生物科技股份有限公司
MCE中国是全球领先的科研化学品和生物活性化合物供应商，总部位于美国新泽西。我们的产品范围覆盖各种抑制剂、激动剂、API和化合物库。专业、高效的企业灵魂铸造了在行业的卓越地位。热情和充满活力的研发团队拥有着大量的化学和生物科学家。专注于生物活性化合物，拥有着多年的发展历程和丰富的行业经验。从产品的HNMR数据解析到生物活性数据，从客户的询价到产品的售后服务，我们拥有着完善的管理体系，从而保证我们的服务更加高效、准确。努力为中国的医药行业发展注入新的活力，我们将成为您研发工作值得信赖的伙伴。

生物活性    
Danoprevir (ITMN-191) is an orally active NS3/4A protease inhibitor for hepatitis C virus (HCV) with an IC50 of 0.29 nM and is selective for NS3/4A over a panel of 53 proteases (IC50 higher than 10 μM). Danoprevir (ITMN-191) inhibits HCV genotypes 1a, 1b, 4, 5, and 6 (IC50s=0.2-0.4 nM) as well as 2b and 3a (IC50s=1.6, 3.5 nM)[1][2]. Danoprevir is also a SARS-CoV 3CLpro inhibitor with an IC50 of 0.05 μM[3].

IC50 & Target    
IC50: 0.29 nM (NS3/4A protease), 0.2-3.5 nM (HCV genotypes 1a, 1b, 2b, 3a, 4, 5, 6)[2]

体外研究(In Vitro)    
In Huh7.5 cells transfected with chimeric recombinant virus, Danoprevir (ITMN-191) shows antiviral inhibition effects against HCV genotypes 1, 4 and 6 with IC50 of 2-3 nM, which are >100-fold lower than genotypes 2/3/5 (280-750 nM)[1].
Danoprevir (ITMN-191) inhibits the reference genotype 1 NS3/4A protease half-maximally, but a high dose of Danoprevir (ITMN-191) (10 μM) shows no appreciably inhibition in a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Danoprevir (ITMN-191) remains bound to and inhibits NS3/4A for more than 5 hours after its initial association. Danoprevir (ITMN-191) (45 nM) eliminates a patient-derived HCV genotype 1b replicon from hepatocyte-derived Huh7 cells with an EC50 of 1.8 nM[2].
In HCV subgenomic replicon cell lines containing the individual mutations, V36M, R109K, and V170A substitutions confer little or no resistance to Danoprevir (ITMN-191), but the R155K substitution confers a high level (62-fold increase) of resistance to Danoprevir[3].

体内研究(In Vivo)    
Danoprevir (ITMN-191) (30 mg/kg, p.o.) administered to rats or monkeys shows that its concentrations in liver 12 hours after dosing exceed the Danoprevir concentration required to eliminate replicon RNA from cells[2].

分子量    
731.83

性状    
Solid

Formula    
C35H46FN5O9S

CAS 号    
850876-88-9

中文名称    
丹诺普韦

运输条件    
Room temperature in continental US; may vary elsewhere.

储存方式    
Powder    -20°C    3 years
4°C    2 years
In solvent    -80°C    6 months
-20°C    1 month
溶解性数据    
In Vitro: 
DMSO : ≥ 100 mg/mL (136.64 mM)

* "≥" means soluble, but saturation unknown.

配制储备液    
浓度溶剂体积质量    1 mg    5 mg    10 mg
1 mM    1.3664 mL    6.8322 mL    13.6644 mL
5 mM    0.2733 mL    1.3664 mL    2.7329 mL
10 mM    0.1366 mL    0.6832 mL    1.3664 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

1.
请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

Solubility: ≥ 2.5 mg/mL (3.42 mM); Clear solution

2.
请依序添加每种溶剂： 10% DMSO    90% corn oil

Solubility: ≥ 2.5 mg/mL (3.42 mM); Clear solution

 

参考文献

[1]. Imhof I, et al. Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors telaprevir (VX-950) and danoprevir (ITMN-191).Hepatology. 2011 Apr;53(4):1090-9.  [Content Brief] [2]. Seiwert, Scott D., et al. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrobial Agents and Chemotherapy (2008), 52(12), 4432-4441. [3]. Bartels DJ, et al. Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis. 2008 Sep 15;198(6):800-7.  [Content Brief] [4]. Qi Sun, et al. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.  [Content Brief]