奧馬曲拉作用機(jī)制 - Medchemexpress - MCE中國

1、Product Data SheetOmapatrilatCat. No.: HY-18208CAS No.: 167305-00-2分式: CHNOS分量: 408.53作靶點(diǎn): Angiotensin-converting Enzyme (ACE)作通路: Metabolic Enzyme/Protease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 : 31 mg/mL (75.88 mM)* means soluble, but saturation unknow

2、n.SolventMass1 mg 5 mg 10 mgConcentration制備儲(chǔ)備液1 mM 2.4478 mL 12.2390 mL 24.4780 mL5 mM 0.4896 mL 2.4478 mL 4.8956 mL10 mM 0.2448 mL 1.2239 mL 2.4478 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

3、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 (6.12 mM); Clear solution此案可獲得 2.5 mg/mL (6.12 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 (6.12 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (6.12 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

5、mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Omapatrilat屬蛋酶ACE和NEP的雙重 抑制劑，Ki值分別為0.64和0.45 nM。IC & Target Ki: 0.45 nM (NEP), 0.64 nM (ACE)1;IC50: 8 nM (NEP), 5 nM (ACE)2體外研究 Omapatrilat exhibits high potency for NEP, NEP2 and ACE, moderate strong activity against APP, but low activityagai

6、nst ECE1 (Ki=0.45, 25, 0.64, 250 nM) 1. In vitro autoradiography using the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A show omapatril at (10 mg/kg) causes rapid and potentinhibition of renal NEP and ACE, respectively, for 24 h4.體內(nèi)研究 Omapatrila

7、t demonstrates excellent blood pressure lowering in a variety of animal models characterized by variouslevels of plasma renin activity and significantly potentiates urinary sodium, ANP, and cGMP excretion in a cynomolgusmonkey assay. Omapatrilat decreases mean arterial pressure (MAP) approximately 4

8、0 mmHg below baseline from 10to 24 h. Oral administration of omapatrilat at 100 M/kg once daily results in a 38 mmHg decrease in systolic bloodpressure at day three as compared to vehicle 2. Omapatrilat is widely used in experimental protocols related tohypertension and heart failure. Chronic oral a

9、dministration of omapatrilat reduces aortic leakiness and atheromaformation with enhanced endothelial independent vasorelaxation to ANP3. Omapatrilat causes significant inhibitionof plasma ACE and increased plasma renin activity in rats4.PROTOCOLKinase Assay 1 Omapatrilat is dissolved in 100% DMSO a

10、t 10 mM and diluted to 1% DMSO. NEP, NEP2, ACE and APP assays areperformed at pH 7.4. The reaction buffer for NEP and NEP2 contained 50 mM HEPES, 140 mM NaCl, 10 mM KCl,0.01% BSA. The buffer for ACE contained 100 mM Tris-HCl, 50 mM NaCl, 10 M ZnCl2, and the buffer for APPcontained 100 mM HEPES and 0

11、.01% BSA. Assays are performed in 100 L volume in black 96-well round-bottomplates at room temperature. Reactions are continuously monitored with excitation and emission wavelengthsappropriate for each respective substrate. Enzyme velocity is determined from the linear part of the reaction1.MCE has

12、not independently confirmed the accuracy of these methods. They are for reference only.Animal Rats: Sprague Dawley rats are weighed and then gavaged with vehicle (5% arabic gum) or omapatrilat (0.1, 1, 10Administration 34 mg/kg) (n 5 6 rats/group). Rats are killed by decapitation at 1 h after gavage

13、. Trunk blood is collected into prechilledtubes containing EDTA/aprotinin for the measurement of PRA and into prechilled heparin tubes for the measurementofplasma ACE4.Rabbits: Omapatrilat is dissolved in drinking water. Rabbits are divided into 2 groups with 1% cholesterol diet,placebo-treated grou

14、p and omapatrilat-treated group, and administrated (12 mg/Kg/day omapatrilat) once daily for8 weeks. To demonstrate the acute effect of omapatrilat, urine is collected after omapatrilat or placeboadministration for 24 hours at day 1, and urine volume, cGMP and ANP levels are assessed3.MCE has not in

15、dependently confirmed the accuracy of these methods. They are for reference only.REFERENCESPage 2 of 3 www.MedChemE1. Fryer RM, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy ofenzymes associated with bradykinin-mediatedangioedema.Br J Pharmacol. 2008

16、Mar;153(5):947-55.2. Robl JA, et al. Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics asinhibitors of angiotensin-convertingenzyme and neutral endopeptidase. J Med Chem. 1997 May 23;40(11):1570-7.3. Ichiki T, et al. Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis. Peptides. 2013Oct;48:21-6.4. Burrell LM, et al. Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hype