格佐匹韦作用机制 - Medchemexpress - MCE中国

1、Product Data SheetGrazoprevirCat. No.: HY-15298CAS No.: 1350514-68-9分式: CHNOS分量: 766.9作靶点: HCV Protease; HCV作通路: Anti-infection; Metabolic Enzyme/Protease储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 50 mg/mL (65.20 mM; Need ultrasonic)H2O : 0.1 mg/mL (insolu

2、ble)SolventMass1 mg 5 mg 10 mgConcentration制备储备液1 mM 1.3040 mL 6.5198 mL 13.0395 mL5 mM 0.2608 mL 1.3040 mL 2.6079 mL10 mM 0.1304 mL 0.6520 mL 1.3040 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；旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 储存时，请在 6 个内使，-20C 储存时，请在 1 个内使。体内实验请根据您的实验动物和给药式

3、选择适当的溶解案。以下溶解案都请先按照 In Vitro 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 的储备液可以根据储存条件，适当保存；体内实验的作液，建议您现现配，当天使； 以下溶剂前显的百分 指该溶剂在您配制终溶液中的体积占；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的式助溶1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.26 mM); Clear solution此案可获得 2.5 mg/mL (3.26 mM，饱和度未知) 的澄清溶液。

4、以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (3.26 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (3.26 mM，饱和度未知) 的澄 溶液，此案不适于实验周 期在半个以上的实验。以 1 mL 作液为例，取 100 L 25.0

5、 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIVITY物活性 Grazoprevir (MK-5172) 选择性的丙型肝炎病毒 NS3/4a蛋酶抑制剂，作于 gt1b，gt1a，gt2a，gt2b 和 gt3a的 K i 分别为 0.01 nM，0.01 nM，0.08 nM，0.15 nM 和 0.90 nM。IC & Target Ki: 0.010.01 nM (gt1b), 0.010.01 nM (gt1a), 0.080.02 nM (gt2a), 0.150.06 nM (gt2b), 0.900.2 nM (gt3a)1体外

6、研究 In biochemical assays, Grazoprevir (MK-5172) is effective against a panel of major genotypes and variants engineeredwith common resistant mutations, with Ki of 0.010.01 nM (gt1b), 0.010.01 nM (gt1a), 0.080.02 nM (gt2a),0.150.06 nM (gt2b), 0.900.2 nM (gt3a), 0.070.01 nM (gt1bR155K), 0.140.03 nM (g

7、t1bD168V), 0.300.04 nM (gt1bD168Y), 5.30.9 nM (gt1bA156T), and 122 nM (gt1bA156V), respectively. In the replicon assay, Grazoprevirdemonstrates subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a, with EC50s of 0.50.1 nM,21 nM, and 21 nM for gt1bcon1, gt1a, and gt2a, respectively. G

8、razoprevir is potent against a panel of HCVreplication mutants NS5A (Y93H) (EC50=0.70.3 nM), NS5B nucleosides (S282T) (EC50=0.30.1 nM), and NS5B(C316Y) (EC50=0.40.2)1. Grazoprevir (MK-5172) maintains the excellent potency against the gt 3a enzyme as well asa broad panel of mutant enzymes, has excell

9、ent potency in the replicon system gt1b IC50(50% NHS)=7.4 nM; gt1a IC50(40% NHS)=7 nM, and shows excellent rat liver exposure2.体内研究 Grazoprevir (MK-5172) demonstrates efficacy in vivo against chronic-HCV-infected chimpanzees1. When dosed todogs, Grazoprevir (MK-5172) shows low clearance of 5 mL/min/

10、kg and a 3 h half-life after iv dosing and has good plasma exposure (AUC=0.4 M h) after a 1 mg/kg oral dose. Dog liver biopsy studies showed that the liverconcentration of Grazoprevir after the 1 mg/kg oral dose is 1.4 M at the 24 h time point. Similar to its behavior inrats, Grazoprevir demonstrate

11、s effective partitioning into liver tissue and maintains high liver concentration, relativeto potency, 24 h after oral dosing in dogs2.PROTOCOLAnimal Rats and Dogs1Administration 1 Studies are performed in both rats and dogs. For studies in which Grazoprevir is dosed intravenously to rats or dogs,th

12、e compound is formulated in polyethylene glycol 200 (PEG200) and administered as a bolus at either 2 mg/kg ofbody weight (Rats) or 0.5 mg/kg (dog). For oral studies, the crystalline potassium salt of the compound is dosed as asolution in PEG400 at 5 mg/kg (Rats) or 1 mg/kg (dog). For all studies, bl

13、ood samples are collected in EDTA-containing tubes at appropriate times and plasma is separated by centrifugation and stored at 70C until analysis.Quantitation of Grazoprevir (MK-5172) levels is conducted by high-performance liquid chromatography/massspectroscopy (LC/MS/MS) following protein precipi

14、tation. Liver samples are obtained from rat studies at thetermination of the experiment. For dog, liver biopsy samples (20 L) are collected following sedation. Tissue samplesare homogenized in four volumes of deionized water, and drug concentrations are determined by LC/MS/MS afterprotein precipitat

15、ion.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献Page 2 of 3 www.MedChemE Nat Biotechnol. 2019 Oct;37(10):1209-1216. Nat Methods. 2018 Jul;15(7):519-522. J Gastroenterol. 2019 May;54(5):449-458. Antivir Res. 2019 Sep. Antiviral Res. 2017 M

16、ar;139:18-24.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. 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 Let