Phosphoramidon-Disodium - Angiotensin-converting Enzyme (ACE) 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPhosphoramidon DisodiumCat. No.: HY-N2021ACAS No.: 164204-38-0分式: CHNNaOP分量: 587.47作靶點(diǎn): Angiotensin-converting Enzyme (ACE); Neprilysin作通路: Metabolic Enzyme/Protease儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C

2、1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) H2O : 140 mg/mL (238.31 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 1.7022 mL 8.5111 mL 17.0221 mL5 mM 0.3404 mL 1.7022 mL 3.4044 mL10 mM 0.1702 mL 0.8511 mL 1.7022 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，并請(qǐng)注意儲(chǔ)備液的保存式和期限。BIOLOGICAL ACTIVITY物活性

3、 Phosphoramidon Disodium屬蛋酶 (metalloprotease) 抑制劑 。抑制內(nèi)素轉(zhuǎn)化酶 (ECE) ，中性肽內(nèi)切酶 (NEP) 和管緊張素轉(zhuǎn)換酶 (ACE) 的IC50 值分別為 3.5 ，0.034 和 78 M。IC50 & Target IC50: 3.5 M (ECE), 34 nM (NEP), 78 M (ACE) 1體外研究Phosphoramidon is a naturally occurring glycopeptide first isolated from a strain of Streptomyces1/3 Master of Smal

4、l Molecules 您邊的抑制劑師www.MedChemEtanashiensis. It has a unique chemical structure featuring a phosphoramidate linkage between a-L-rhamnoseand L-leucineL-tryptophan. As a microbial metabolite, phosphoramidon exhibits potent inhibitory activityagainst thermolysin, a zinc endopeptidase isolated from Baci

5、llus thermoproteolyticus (Ki=32 nM) 2.體內(nèi)研究 Intranasal administration of phosphoramidon produces significantly elevated cerebral A levels in wild-typemice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP andNEP2 also shows increased levels of A40 3. Phosphora

6、midon blocks the formation of endothelin-1 (ET-1),a proinflammatory mediator implicated in the pathogenesis of a variety of lung diseases. Phosphoramidonsignificantly reduces LPS-induced pulmonary inflammation as measured by lung histology, neutrophil contentof bronchoalveolar lavage (BAL) fluid, pe

7、rcent tumor necrosis factor receptor 1 (TNFR1)-labeled BALmacrophages, and alveolar septal cell apoptosis 4. Phosphoramidon significantly decreased ET-1 levels,causing a concomitant big ET-1 increase and dose-dependently attenuated indomethacin-induced gastricmucosal damage 5.PROTOCOLKinase Assay 2

8、The Ki values are determined in a 50 mM Tris-HCl, 10 mM CaCl2 buffer (pH 7.5) with FA-Gly-Leu-NH2(FAGLA) as a substrate by using an Agilent 8453 UV-vis spectrophotometer in triplicate. Henderson plots areemployed for the calculation of Ki values. A mixture of buffer (970 L), phosphoramidon (0-80 nM,

9、 20 L),and thermolysin (40 nM, 10 L) is incubated at 25 C for 15 min in a cuvette (2 mL). A solution of FAGLA (0.1-0.5 mM, 1.0 mL) in Tris buffer pH 7.5 is added into the cuvette. The absorbance decrease upon cleavage ofFAGLA by thermolysinis recorded at 340 nm wavelength for 5 min. The concentratio

10、n of thermolysinisdetermined from the molar extinction coefficient 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 3Administration 34 Phosphoramidon is dissolved in phosphate-buffered saline (PBS+1 mM ascorbic acid) at a concentration of30

11、 mM. Anesthetized mice are placed on their backs and eight 3-L drops of phosphoramidon solution areadministered to alternating nares every 2 min. This is done once per day for 5 days. Mice are euthanizedunder anesthesia for tissue collection 2 h post phosphoramidon administration on day 5. Control m

12、ice aretreated with intranasal PBS vehicle solution alone. Brains are removed and dissected into the desired brainregions before being homogenized in 5 M guanidine HCl to extract total A. After centrifugation (16,000g),the supernatants are diluted tenfold and A (1-42 and 1-40) is quantified by speci

13、fic ELISA.Rats 4Animals are treated with phosphoramidon either intraperitoneally or intratracheally via nebulization. Toexamine the effects of intraperitoneal administration, animals are injected with 0.5 mg of phosphoramidondissolved in 0.5 mL of phosphatebuffered saline (PBS). For the nebulization

14、 studies, animals are placed in anexposure chamber and treated for 1 hour with an aerosol composed of a 0.1% solution of phosphoramidondissolved in distilled water. The aerosolized phosphoramidonis delivered through a ceiling port via a Misty-Oxnebulizer attached to an air compressor. Negative press

15、ure is applied by a blower attached to a secondaryoutflow port to insure proper circulation of the aerosol.MCE has not independently confirmed the accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEREFERENCES1. Kukkola PJ, et al. Differential stru

16、cture-activity relationships of phosphoramidon analogues for inhibition of three metalloproteases:endothelin-converting enzyme, neutral endopeptidase, and angiotensin-converting enzyme.J CardiovascPharmacol. 1995;26Suppl 3:S65-8.2. Sun Q, et al. Synthesis and enzymatic evaluation of phosphoramidon a

17、nd its anomer: Anomerization of -l-rhamnose triacetate uponphosphitylation.Bioorg Med Chem. 2013 Nov 1;21(21):6778-87.3. Hanson LR, et al. Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice.J MolNeurosci.2011 Mar;43(3):424-7.4. Bhavsar TM, et al. Phosphoramidon, an endothelin-converting enzyme inhibitor, attenuates lipopolysaccharide-induced acute lunginjury.Exp Lung Res. 2008 Mar;34(3):141-54.5. Matsumaru K, et al. Phosphoramidon, an inhibitor of endothelin-converting enzyme, prevents indomethaci