達(dá)卡他韋作用機(jī)制 - Medchemexpress - MCE中國(guó)

1、Product Data SheetDaclatasvirCat. No.: HY-10466CAS No.: 1009119-64-5分式: CHNO分量: 738.88作靶點(diǎn): HCV作通路: Anti-infection儲(chǔ)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(shí)驗(yàn) DMSO : 40 mg/mL (54.14 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制備

2、儲(chǔ)備液1 mM 1.3534 mL 6.7670 mL 13.5340 mL5 mM 0.2707 mL 1.3534 mL 2.7068 mL10 mM 0.1353 mL 0.6767 mL 1.3534 mL請(qǐng)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(chǔ)備液；旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)內(nèi)使，-20C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)內(nèi)使。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍浮Ｒ韵氯芙獍付颊?qǐng)先按照 In Vitro 式配制澄清的儲(chǔ)備液，再依次添加助

3、溶劑：為保證實(shí)驗(yàn)結(jié)果的可靠性，澄 的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)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(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的式助溶1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.38 mM); Clear solution此案可獲得 2.5 mg/mL (3.38 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到

4、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(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (3.38 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (3.38 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻

5、。3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (3.38 mM); Clear solution此案可獲得 2.5 mg/mL (3.38 mM，飽和度未知) 的澄 溶液，此案不適于實(shí)驗(yàn)周 期在半個(gè)以上的實(shí)驗(yàn)。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Daclatasvir種有效的 HCV NS5A 抑制劑，作于 因型 1a 和 1b 復(fù)制，平均 EC50 為 50 和 9 pM。IC & Target

6、EC50: 94 pM (HCV replicon genotype 1b, in Con1 cells), 50 13 pM (HCV replicon genotype 1a, in H77 cells)1體外研究 Daclatasvir (BMS-790052) is a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range

7、 of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. Daclatasvir is a potent inhibitor of the JFH-1 genotype 2a infectious virusthat replicates in cell culture (EC50=28 pM), an assay considered to be a more biologically relevant in vitro cell culturesystem. In addition, Dacl

8、atasvir displays similar potency in Huh-7, HeLa and HEK293T cells, demonstrating that thefunction(s) of NS5A inhibited by Daclatasvir is (are) highly conserved in different cellular environments1.體內(nèi)研究 In a randomized, double-blind, placebo-controlled, single ascending-dose study, Daclatasvir (BMS-79

9、0052) isadministered at six dose levels to healthy, non-HCV-infected subjects over a range of 1 to 200 mg as an oral solution.Daclatasvir is safe and well tolerated up to 200 mg with no clinically relevant adverse effects. After oral administration,Daclatasvir is readily absorbed, with dose-proporti

10、onal exposures over the studied dose range, and all subjects havedrug concentrations greater than the protein-binding-adjusted EC90 for genotypes 1a and 1b, as measured in thereplicon assay, at and beyond 24 h post-dose. (The protein binding-adjusted EC90 figures are derived from an analysisof the e

11、ffect of the addition of human serum on antiviral activity in replicons. In the presence of 40% human serum,the EC90 for Daclatasvir is 383 pM (0.28 ng/mL) for the genotype 1a replicon and 49 pM (0.04 ng/mL) for thegenotyope 1b replicon)1. Mice in each group that developed persistent HCV infection a

12、re divided into two treatmentgroups. One group receive 4 weeks of Asunaprevir/Daclatasvir treatment and the other group received 4 weeks ofLedipasvir/GS-558093 treatment. Asunaprevir/Daclatasvir therapy and Ledipasvir/GS-558093 therapy rapidly deceaseserum HCV RNA levels to below the sensitivity, an

13、d they are not detected after completion of the therapy except fortwo mice in the Ledipasvir/GS-558093 group2.PROTOCOLCell Assay 1 HCV genotype 1a and 1b replicon cells are maintained in media containing Daclatasvir at a concentration of 5- to 20-fold above EC50 and 0.5 mg/mL G418. Replicon cells si

14、milarly treated with DMSO are maintained as controls. Afterapproximately 4-5 weeks when cell growth is similar to DMSO-treated control cells, selected cells are expanded forresistance testing and analysis by PCR with reverse transcription1.MCE has not independently confirmed the accuracy of these me

15、thods. They are for reference only.Animal Mice2Administration 2 Humanized liver chimeric mice, whose chimeric rate of the liver is estimated as over 40 %, are injected intravenouslywith 100 L of HCV-positive human serum samples. After inoculation, their blood is collected from an externaljugular vei

16、n every 1-4 weeks. The HCV RNA levels are measured by the COBAS TaqMan HCV test in 100-fold dilutedPage 2 of 3 www.MedChemEserum with a lower measurement range of 3.2 log IU/mL serum. After serum levels of HCV RNA reach plateau levels,mice are administered orally once a day for 4 weeks with one of t

17、he following: 40 mg/kg of Asunaprevir plus 30mg/kg of Daclatasvir, 15 mg/kg of Ledipasvir plus 50 mg/kg of GS-558093 and 50 mg/kg of GS-558093 plus 400mg/kg of Telaprevir.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Hepatology. 2019 May;6

18、9(5):1861-1872. EMBO Rep. 2016 Jul;17(7):1013-28. PLoS Pathog. 2018 Sep 18;14(9):e1007284. PLoS Pathog. 2017 May 11;13(5):e1006374. Int J Radiat Oncol Biol Phys. 2016 Nov 15;96(4):867-876.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Gao M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010 May 6;465(7294):96-100.2. Kai Y, et al. Emergence of hepatiti