維沙莫德作用機制 - Medchemexpress - MCE中國

1、Product Data SheetVesatolimodCat. No.: HY-15601CAS No.: 1228585-88-3分式: CHNO分量: 410.51作靶點: Toll-like Receptor (TLR); Apoptosis; HBV; HCV; HIV作通路: Immunology/Inflammation; Apoptosis; Anti-infection儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 16.67 mg/mL (40.6

2、1 mM)H2O : 0.1 mg/mL (insoluble)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制備儲備液1 mM 2.4360 mL 12.1800 mL 24.3599 mL5 mM 0.4872 mL 2.4360 mL 4.8720 mL10 mM 0.2436 mL 1.2180 mL 2.4360 mL請根據(jù)產(chǎn)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(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months

3、; -20C, 1 month。-80C 儲存時，請在 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?。以下溶解案都請先按?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(jù)儲存條件，適當保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)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(xiàn)沉淀、析出現(xiàn)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: 1.67

4、 mg/mL (4.07 mM); Clear solution此案可獲得 1.67 mg/mL (4.07 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 16.699999 mg/mL 的澄清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(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 1.67 mg/mL (4.07 mM); Suspended solution; Need ul

5、trasonicPage 1 of 2 www.MedChemE此案可獲得 1.67 mg/mL (4.07 mM) 的均勻懸濁液，懸濁液可于服和腹腔注射。以 1 mL 作液為例，取 100 L 16.699999 mg/mL 的澄 DMSO 儲備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 1.67 mg/mL (4.07 mM); Clear solution此案可獲得 1.67 mg/mL (4.07 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

6、 1 mL 作液為例，取 100 L 16.699999 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Vesatolimod (GS-9620)種有效，選擇性，可服的 Toll 樣受體7 (TLR7) 激動劑，EC50 值為291 nM。IC & Target EC50: 291 nM (TLR7), 9 M (TLR8)3體外研究 Vesatolimod (GS-9620) rapidly internalizes into cells and preferentially localizes to and signals

7、 from endo-lysosomalcompartments. To test this hypothesis, the kinetics of cellular uptake of the compound in Daudi cells using tritiatedVesatolimod (3H-GS-9620) is measured. The kinetics of 3H-GS-9620 accumulation is rapid, reaching concentration-dependent steady-state equilibrium in approximately

8、thirty minutes. Measured intracellular concentration of 3H-Vesatolimod is 5-fold higher than the extracellular concentration of 3H-GS-9620 used to treat cells. Increases inintracellular 3H-Vesatolimod concentrations are roughly proportional with increasing concentrations of 3H-GS-96201.體內(nèi)研究 Single o

9、ral doses of Vesatolimod (GS-9620) at 0.3 and 1 mg/kg in uninfected chimpanzees demonstrates a dose- andexposure-related induction of serum IFN-, select cytokines/chemokines, and IFN-stimulated genes (ISG) in theperipheral blood and liver. Following oral administration at 0.3 (n=3), and 1 mg/kg (n=3

10、 and n=4), Vesatolimod (GS-9620) Cmax is 3.63.5, 36.834.5, and 55.481.0 nM, respectively. Peak serum IFN responses occur at 8 h post-dose.The mean peak levels of induced serum IFN- are 66 and 479 pg/mL at doses of 0.3 and 1 mg/kg, respectively.Vesatolimod (GS-9620) treatment induces ISG transcripts

11、including ISG15, OAS-1, MX1, IP-10 (CXCL10), and I-TAC(CXCL11) in peripheral blood mononuclear cells (PBMC) at 0.3 mg/kg and in both PBMC and the liver at 1 mg/kg2.PROTOCOLCell Assay 1 Daudi cells are incubated for indicated times with varying concentrations 3HVesatolimod (GS-9620) (0.7Ci/mL). Cella

12、ssociated radioactivity is extracted with ice cold 80% ethanol and measured using liquid scintillation counting. Thetotal amount of Vesatolimod in cells is calculated from a calibration curve for Vesatolimod (GS-9620) mass versusradioactivity. Cell volume is measured1.MCE has not independently confi

13、rmed the accuracy of these methods. They are for reference only.Animal Chimpanzee2Administration 2 Chimpanzees are used. The trial design includes 4 weeks of pre-study evaluation (Day-28, -13 and just prior to firstdose) and two cycles of oral Vesatolimod (GS-9620) treatment every other day three ti

14、mes per week for 4 weeks withone cycle at 1 mg/kg, and, after a one week rest, a second cycle at 2 mg/kg. Animals are also intensely monitored for14 weeks after treatment to assess tolerability and durability of response.MCE has not independently confirmed the accuracy of these methods. They are for

15、 reference only.Page 2 of 3 www.MedChemE戶使本產(chǎn)品發(fā)表的科研獻 Nat Biomed Eng. 2018;2:578-588. Front Microbiol. 2018 Sep 19;9:2022. Antiviral Res. 2018 Feb 6;153:39-48. Vaccine. 2018 Feb 1;36(6):794-801. Drug Test Anal. 2019 Feb;11(2):240-249.See more customer validations on HYPERLINK www.MedChemE www.MedChemE

16、REFERENCES1. Rebbapragada I, et al. Molecular Determinants of GS-9620-Dependent TLR7 Activation. PLoS One. 2016 Jan 19;11(1):e0146835.2. Lanford RE, et al. GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically InfectedChimpanzees. Gastroenterology. 2013 Feb 13. pii: S0016-5085(13)00169-8.3. D Tumas, et al. Preclinical Characterization of GS-9620, A Potent and Se