安倍生坦作用機(jī)制 - Medchemexpress - MCE中國(guó)

1、Product Data SheetAmbrisentanCat. No.: HY-13209CAS No.: 177036-94-1分式: CHNO分量: 378.42作靶點(diǎn): Endothelin Receptor作通路: GPCR/G Protein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 : 100 mg/mL (264.26 mM; Need ultrasonic)Ethanol : 7.14 mg/mL (18.87 mM; Need ultrasonic

2、)SolventMass1 mg 5 mg 10 mgConcentration制備儲(chǔ)備液1 mM 2.6426 mL 13.2128 mL 26.4257 mL5 mM 0.5285 mL 2.6426 mL 5.2851 mL10 mM 0.2643 mL 1.3213 mL 2.6426 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

3、適當(dāng)?shù)娜芙獍?。以下溶解案都?qǐng)先按照 In Vitro 式配制澄清的儲(chǔ)備液，再依次添加助溶劑：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(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.61 mM); Clear solution此案可獲得 2.5 mg/mL (6.61 mM，飽和度未知) 的澄清溶液。以

4、1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)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(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.61 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (6.61 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 m

5、g/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 油中，混合均勻。3. 請(qǐng)依序添加每種溶劑： 10% EtOH 40% PEG300 5% Tween-80 45% salineSolubility: 0.71 mg/mL (1.88 mM); Clear solution此案可獲得 0.71 mg/mL (1.88 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 7.1 mg/mL 的澄 EtOH 儲(chǔ)備液加到 400 L PEG300 中，混合均勻；向上述體系中加 50L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。4. 請(qǐng)依序添加每種溶劑

6、： 10% EtOH 90% (20% SBE-CD in saline)Solubility: 0.71 mg/mL (1.88 mM); Clear solution此案可獲得 0.71 mg/mL (1.88 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 7.1 mg/mL 的澄 EtOH 儲(chǔ)備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。5. 請(qǐng)依序添加每種溶劑： 10% EtOH 90% corn oilSolubility: 0.71 mg/mL (1.88 mM); Clear solution此案可獲得 0.71 mg/mL (1

7、.88 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 7.1 mg/mL 的澄 EtOH 儲(chǔ)備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Ambrisentan種選擇性的ET A型受體 (ETAR) 拮抗劑。IC & Target ETA receptor1體外研究 Ambrisentan is an endothelin type A receptor antagonist1. Ambrisentan induces Nrf2 activation. Endothelialpermeabil

8、ity increased in BMEC monolayers at 24 h of hypoxia exposure and compared to vehicle control,Ambrisentan attenuates hypoxia-induced BMEC leak. These results are reversed when prior to treatment BMEC aretransfected with siRNA against Nrf22.體內(nèi)研究 In the Ambrisentan group, hepatic hydroxyproline content

9、 is significantly lower than in the control group (18.0 g/g6.1 g/g vs 33.9 g/g13.5 g/g liver, respectively, P=0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for -smooth muscle actin, indicative of activated hepatic stellate cells, are also significantly lowerin the Ambr

10、isentan group (0.46%0.18% vs 1.11%0.28%, respectively, P=0.0003; and 0.12%0.08% vs 0.25%0.11%,respectively, P=0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor ofmetalloproteinase-1 (TIMP-1) are significantly lower by 60% and 45%, respectively, in the Ambrisentan

11、group.Inflammation, steatosis, and endothelin-related mRNA expression in the liver are not significantly different betweenthe groups. Ambrisentan attenuates the progression of hepatic fibrosis by inhibiting hepatic stellate cell activationand reducing procollagen-1 and TIMP-1 gene expression. Ambris

12、entan did not affect inflammation or steatosis1.PROTOCOLCell Assay 2 Unless otherwise stated, for each BMEC experiment cells are randomly divided into 4 groups: (1) normoxia vehiclecontrol (Nx-CTRL); (2) normoxia-treated; (3) hypoxia (24 h) control (Hx-CTRL) and (4) hypoxia (24 h) treated. Aspreviou

13、sly described, Nrf2 activators are added 24 h prior to any hypoxic exposures. Cell treatments are; Protandim(100 g/mL), methazolamide (125 g/mL, nifedipine (7 g/mL) or Ambrisentan (40 g/mL). In addition, some cells aretreated with Nrf2 siRNA. In these experiments, siRNA is added 24 h prior to drug t

14、reatments. The rationale for 24 hPage 2 of 3 www.MedChemEhypoxia exposure for BMEC is to ensure that cells remained transfected with siRNA for the pre-treatment of drugs (24h in normoxia) and during the 24 h hypoxia exposure. Data is collected from at least three separate cell culturepreparations on

15、 three separate days (n=9)2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice1Administration 1 A total of 13 male FLS-ob/ob mice (age, 8 wk; body weight, 42.88 g1.74 g) are used. At the age of 12 wk, male FLS-ob/ob mice are randomly assigned t

16、o the Ambrisentan (n=8) or control (n= 5) group. Intragastric gavageadministration is carried out in conscious animals with an appropriately sized gastric tube. Ambrisentan (2.5 mg/kgper day) is orally administered every afternoon for 4 wk as a bolus through a gastric tube. Water is administered tot

17、he control group. At week 4, animals are fasted for 4 h and tail vein blood is drawn and subjected to blood glucosedetermination. Animals are killed by pentobarbital anesthesia injection after 4 wk and blood is collected from theright ventricle. Plasma samples are frozen and stored at -80C Liver and

18、 visceral fat are then weighed, snap-frozen inliquid nitrogen, and stored at -80C. Additional liver specimens are fixed in 10% buffered formalin and embedded inparaffin for histological analysis.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Okamoto T, et al. Antifibrotic effects of Ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model. World JHepatol. 2016 Aug 8;8(22):933-41.2. Lisk C, et al. Nrf2 activation: a potential strategy for the prevention of a