1、Product Data SheetGrazoprevirCat. No.: HY-15298CAS No.: 1350514-68-9分式: CHNOS分量: 766.9作靶點: HCV Protease; HCV作通路: Anti-infection; Metabolic Enzyme/Protease儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數據體外實驗 DMSO : 50 mg/mL (65.20 mM; Need ultrasonic)H2O : 0.1 mg/mL (insolu

2、ble)SolventMass1 mg 5 mg 10 mgConcentration制備儲備液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請根據產品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復凍融造成的產品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內使，-20C 儲存時，請在 1 個內使。體內實驗請根據您的實驗動物和給藥式

3、選擇適當的溶解案。以下溶解案都請先按照 In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結果的可靠性，澄 的儲備液可以根據儲存條件，適當保存；體內實驗的作液，建議您現現配，當天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現沉淀、析出現象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.26 mM); Clear solution此案可獲得 2.5 mg/mL (3.26 mM，飽和度未知) 的澄清溶液。

4、以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (3.26 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (3.26 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 25.0

5、 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Grazoprevir (MK-5172) 選擇性的丙型肝炎病毒 NS3/4a蛋酶抑制劑，作于 gt1b，gt1a，gt2a，gt2b 和 gt3a的 K i 分別為 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體外

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.體內研究 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.戶使本產品發表的科研獻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