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850876-88-9 分子结构
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(1S,4R,6S,7Z,14S,18R)-14-{[(tert-butoxy)carbonyl]amino}-4-(cyclopropanesulfonamidomethyl)-2,15-dioxo-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-en-18-yl 4-fluoro-2,3-dihydro-1H-isoindole-2-carboxylate

ChemBase编号:72565
分子式:C35H48FN5O8S
平均质量:717.8477232
单一同位素质量:717.32076274
SMILES和InChIs

SMILES:
[C@@H]1(CN2[C@@H](C1)C(=O)N[C@@]1(CNS(=O)(=O)C3CC3)[C@H](C1)/C=C\CCCCC[C@@H](C2=O)NC(=O)OC(C)(C)C)OC(=O)N1Cc2c(C1)c(ccc2)F
Canonical SMILES:
O=C(OC(C)(C)C)N[C@H]1CCCCC/C=C\[C@@H]2[C@@](NC(=O)[C@H]3N(C1=O)C[C@@H](C3)OC(=O)N1Cc3c(C1)cccc3F)(CNS(=O)(=O)C1CC1)C2
InChI:
InChI=1S/C35H48FN5O8S/c1-34(2,3)49-32(44)38-28-13-8-6-4-5-7-11-23-17-35(23,21-37-50(46,47)25-14-15-25)39-30(42)29-16-24(19-41(29)31(28)43)48-33(45)40-18-22-10-9-12-27(36)26(22)20-40/h7,9-12,23-25,28-29,37H,4-6,8,13-21H2,1-3H3,(H,38,44)(H,39,42)/b11-7-/t23-,24-,28+,29+,35+/m1/s1
InChIKey:
NLLUOMDMSMVXKN-UIOHFMAFSA-N

引用这个纪录

CBID:72565 http://www.chembase.cn/molecule-72565.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
(1S,4R,6S,7Z,14S,18R)-14-{[(tert-butoxy)carbonyl]amino}-4-(cyclopropanesulfonamidomethyl)-2,15-dioxo-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-en-18-yl 4-fluoro-2,3-dihydro-1H-isoindole-2-carboxylate
IUPAC传统名
(1S,4R,6S,7Z,14S,18R)-14-[(tert-butoxycarbonyl)amino]-4-(cyclopropanesulfonamidomethyl)-2,15-dioxo-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-en-18-yl 4-fluoro-1,3-dihydroisoindole-2-carboxylate
别名
RG7227
ITMN-191
RO5190591
Danoprevir(ITMN-191)
CAS号
850876-88-9
PubChem SID
162037490
PubChem CID
46931004

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S1183 external link 加入购物车 请登录
数据来源 数据ID
PubChem 46931004 external link

理论计算性质

理论计算性质

JChem
Acid pKa 10.380437  质子受体
质子供体 LogD (pH = 5.5) 2.608198 
LogD (pH = 7.4) 2.6078007  Log P 2.608203 
摩尔折射率 181.667 cm3 极化性 71.2188 Å3
极化表面积 163.45 Å2 可自由旋转的化学键
里宾斯基五规则 false 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
DMSO expand 查看数据来源
保存条件
-20°C expand 查看数据来源
作用靶点
protease expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S1183 external link
Research Area
Description Hepatitis C
Biological Activity
Description Danoprevir is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM.
Targets HCV NS3/4A protease
IC50 0.2-3.5 nM [1]
In Vitro Danoprevir (0.29 nM) inhibits the reference genotype 1 NS3/4A protease half-maximally, but a high dose of Danoprevir (10 μM) shows no appreciably inhibition in a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Danoprevir remains bound to and inhibits NS3/4A for more than 5 hours after its initial association. Danoprevir (45 nM) eliminates a patient-derived HCV genotype 1b replicon from hepatocyte-derived Huh7 cells with an EC50 of 1.8 nM. [1]In HCV subgenomic replicon cell lines containing the individual mutations, V36M, R109K, and V170A substitutions confer little or no resistance to Danoprevir, but the R155K substitution confers a high level (62-fold increase) of resistance to Danoprevir. [2]In Huh7.5 cells transfected with chimeric recombinant virus, Danoprevir 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). [3]
In Vivo Danoprevir (30 mg/kg) 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. [1]
Clinical Trials Danoprevir, associated with RO5024048, is currently under investigation in Phase II clinical trials in genotype 1 chronic hepatitis C.
Features Danoprevir is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV).
Protocol
Kinase Assay [1]
Continuous fluorescent resonance energy transfer (FRET) assay The assay buffer contains 25 μM NS4A peptide, 50 mM Tris-HCl, pH 7.5, 15% (vol/vol) glycerol, 0.6 mM lauryldimethylamine N-oxide, 10 mM dithiothreitol, and 0.5 μM fluorescein/QXL520-labeled FRET substrate {Ac-DE-Dap(QXL520)-EE-Abu-ψ-[COO]-AS-Cys(5-FAMsp)-NH2}. K2040 enzyme (50 pM) is added to initiate the reaction. Reactions are set up in black 96-well plates, and fluorescence data is collected. Control reactions lacking inhibitors and enzyme are included. Initial rates are calculated from the linear phase of the reaction (up to 1 hour) and are used to obtain IC50. Recovery of activity from preformed Danoprevir-NS3/4A complex is assessed by preincubating 10 nM NS3/4A with a two-fold excess of Danoprevir in 1× assay buffer for 15 min, followed by a rapid 200-fold dilution of the preformed complex into assay buffer containing substrate. A control reaction with the same final conditions without preincubation of NS3/4A and Danoprevir is initiated by the addition of enzyme to an otherwise-complete reaction mixture. Additional control reactions lack either Danoprevir or NS3. The progress of the reactions is followed over 5 hours.
Cell Assay [1]
Cell Lines Huh7 cells harboring HCV replicon
Concentrations 5 pM - 100 nM
Incubation Time 48 hours
Methods Serially diluted Danoprevir is added to Huh7 cells harboring the K2040 replicon 1 day after cell plating. For antiviral assays, after a 48-hour incubation, intracellular RNA is extracted, and the level of HCV replicon RNA is quantified by reverse transcription (RT)-PCR assay with the primers (5’-CACTCCCCTGTGAGGAACTACTG-3’ and 5’-AGGCTGCACGACACTCATACT-3’) and a probe (5’-6-FAM-CTTCACGCAGAAAGCGTCTAGCCATGG-MGBNFQ-3’ using an ABI Prism 7900 sequence detection system. Here, FAM is 6-carboxyfluorescin and MGBNFQ is a molecular-groove binding non-fluorescence quencher specific to the HCV 5’ untranslated region. Single-tube reactions are performed using the TaqMan Gold RT-PCR kit. Triplicate reactions for the RNA standards and samples are performed in 50 μL with 5 μL intracellular RNA (50 ng). RT is carried out at 48 °C for 30 min followed by 10 min at 95 °C. The PCR is run as follows: 15 seconds at 95 °C and 1 min at 60 °C for 40 cycles. Each RNA concentration is determined in triplicate. The absolute concentration of replicon RNA is calculated based on its signal relative to that of a standard curve generated by known concentrations of an in vitro-transcribed RNA corresponding to a genotype 1b 5’ untranslated region. Replicon levels in the presence of Danoprevir are fitted to a four-parameter logistic function to obtain EC50.
Animal Study [1]
Animal Models Sprague-Dawley rats, Cynomolgus monkeys
Formulation Dissolved in water. 6 mg/mL for rats and 3 mg/mL for monkeys
Doses 30 mg/kg
Administration Oral gavage
References
[1] Seiwert SD, et al. Antimicrob Agents Chemother, 2008, 52(12), 4432-4441.
[2] Bartels DJ, et al. J Infect Dis, 2008, 198(6), 800-807.
[3] Imhof I, et al. Hepatology, 2011, 53(4), 1090-1099.

参考文献

参考文献

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