Omapatrilat (BMS-186716)
(Synonyms: BMS-186716) 目录号 : GC34019
An ACE and NEP inhibitor
Cas No.:167305-00-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Kinase experiment: |
Omapatrilat is dissolved in 100% DMSO at 10 mM and diluted to 1% DMSO. NEP, NEP2, ACE and APP assays are performed 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 μM ZnCl2, and the buffer for APP contained 100 mM HEPES and 0.01% BSA. Assays are performed in 100 μL volume in black 96-well round-bottom plates at room temperature. Reactions are continuously monitored with excitation and emission wavelengths appropriate for each respective substrate. Enzyme velocity is determined from the linear part of the reaction[1]. |
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Animal experiment: |
Rats: Sprague Dawley rats are weighed and then gavaged with vehicle (5% arabic gum) or omapatrilat (0.1, 1, 10 mg/kg) (n 5 6 rats/group). Rats are killed by decapitation at 1 h after gavage. Trunk blood is collected into prechilled tubes containing EDTA/aprotinin for the measurement of PRA and into prechilled heparin tubes for the measurement ofplasma ACE[4]. Rabbits: Omapatrilat is dissolved in drinking water. Rabbits are divided into 2 groups with 1% cholesterol diet, placebo-treated group and omapatrilat-treated group, and administrated (12 mg/Kg/day omapatrilat) once daily for 8 weeks. To demonstrate the acute effect of omapatrilat, urine is collected after omapatrilat or placebo administration for 24 hours at day 1, and urine volume, cGMP and ANP levels are assessed[3]. |
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References: [1]. Fryer RM, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy ofenzymes associated with bradykinin-mediated angioedema.Br J Pharmacol. 2008 Mar;153(5):947-55. |
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Omapatrilat is an orally bioavailable angiotensin-converting enzyme (ACE) and neprilysin (NEP) inhibitior (IC50s = 1.7 and 5.3 nM, respectively, for the human enzymes).1 It inhibits the pressor response induced by angiotensin I in normotensive rats (ED50 = 0.07 ?mol/kg) and lowers mean arterial pressure (MAP) in sodium-depleted spontaneously hypertensive rats when administered at a dose of 30 ?mol/kg.2 Omapatrilat lowers MAP in rats when co-administered with bradykinin .3 It also increases tracheal plasma extravasation in a rat model of upper airway angioedema in a dose-dependent manner.4
1.Sulpizio, A.C., Pullen, M.A., Edwards, R.M., et al.Mechanism of vasopeptidase inhibitor-induced plasma extravasation: Comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-converting enzyme inhibitor GW796406J. Pharmacol. Exp. Ther.315(3)1306-1313(2005) 2.Robl, J.A., Sun, C.-Q., Stevenson, J., et al.Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidaseJ. Med. Chem.40(11)1570-1577(1997) 3.Fryer, R.M., Segreti, J., Banfor, P.N., et al.Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: Rank efficacy of enzymes associated with bradykinin-mediated angioedemaBr. J. Pharmacol.153(5)947-955(2008) 4.Murray McKinnell, R., Fatheree, P., Choi, S.-K., et al.Discovery of TD-0212, an orally active dual pharmacology AT1 antagonist and neprilysin inhibitor (ARNI)ACS Med. Chem. Lett.10(1)86-91(2018)
| Cas No. | 167305-00-2 | SDF | |
| 别名 | BMS-186716 | ||
| Canonical SMILES | O=C([C@@H]1CCC[C@](N21)([H])SCC[C@H](NC([C@@H](S)CC3=CC=CC=C3)=O)C2=O)O | ||
| 分子式 | C19H24N2O4S2 | 分子量 | 408.53 |
| 溶解度 | DMSO : ≥ 31 mg/mL (75.88 mM) | 储存条件 | Store at -20°C, protect from light, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4478 mL | 12.239 mL | 24.478 mL |
| 5 mM | 0.4896 mL | 2.4478 mL | 4.8956 mL |
| 10 mM | 0.2448 mL | 1.2239 mL | 2.4478 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Neprilysin inhibition in chronic kidney disease
Nephrol Dial Transplant 2015 May;30(5):738-43.PMID:25140014DOI:10.1093/ndt/gfu269.
Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (Omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.
Renal events in patients receiving neprilysin inhibitors: a systematic review and meta-analysis
Nephrol Dial Transplant 2022 Nov 23;37(12):2418-2428.PMID:35022763DOI:10.1093/ndt/gfac001.
Background: While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. Methods: We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or Omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. Results: Overall, treatment with sacubitril/valsartan or Omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)]. Conclusion: NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.
Omapatrilat: a unique new agent for the treatment of cardiovascular disease
Heart Dis 2000 May-Jun;2(3):266-74.PMID:11728268doi
Omapatrilat is the most clinically advanced of a new class of drugs, vasopeptidase inhibitors, which are being studied for the treatment of patients with cardiovascular disease. Omapatrilat inhibits the enzymatic activities of angiotensin-converting enzyme and neutral endopeptidase. The end result is blockade of angiotensin-II formation and inhibition of the catabolism of vasodilatory hormones, such as the natriuretic peptides, bradykinin, and adrenomedullin. Some of the ultimate pharmacologic effects include vasodilation, natriuresis, and diuresis, which may be beneficial in the management of various cardiovascular diseases, such as hypertension and heart failure. The pharmacokinetics of Omapatrilat are compatible with once-daily dosing and a duration of antihypertensive efficacy of more than 24 hours. Omapatrilat decreases blood pressure in both high-renin and low-renin states, which suggests antihypertensive efficacy that is independent of the status of the renin-angiotensin system. Furthermore, the antihypertensive effect of Omapatrilat is indiscriminate of age or race. Omapatrilat has consistently shown efficacy in decreasing both systolic and diastolic blood pressure to a similar or greater extent than either lisinopril or amlodipine; however, systolic pressure is more responsive to Omapatrilat treatment than diastolic pressure. Although the role of Omapatrilat in heart failure is still evolving, preliminary results are promising: hemodynamic improvements and clinical benefits of Omapatrilat are similar or greater to those achieved with an angiotensin-converting enzyme inhibitor. Future studies (specifically the OVERTURE Study) will be of pivotal importance in establishing the role of Omapatrilat in the treatment of patients with heart failure. The side-effect and drug-interaction profiles of Omapatrilat are largely incomplete, but suggest excellent tolerability and a side-effect profile that is similar to placebo. Omapatrilat could be a revolutionary addition to the management of cardiovascular disease, and its clinical development will be followed closely by many who are curious if larger clinical trials will echo the impressive preliminary data that have been seen thus far.
Omapatrilat. Bristol-Myers Squibb
Curr Opin Investig Drugs 2001 Oct;2(10):1414-22.PMID:11890357doi
Bristol-Myers Squibb (BMS) is developing the vasopeptidase inihibitor, Omapatrilat, a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), for the potential treatment of cardiovascular diseases such as hypertension and heart failure [306287]. An NDA for the use of Omapatrilat in hypertension was filed with the FDA and the regulatory authorities in the EU in December 1999 [351207], [353287]. In April 2000, BMS voluntarily withdrew the NDA in response to questions raised by the FDA regarding the comparative incidence and severity of an infrequent side effect (angioedema) reported within the NDA database. Prospective controlled clinical studies in patients with hypertension and heart failure were to continue. In May 2001, BMS reported that its blinded Omapatrilat hypertension study was continuing and, pending supportive results from a data analysis anticipated in late summer/early autumn 2001, the company expected to refile an NDA with the FDA [409203]. In July 2000, BMS reported that it planned to conduct a multinational, 25,000 patient study (OCTAVE - Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) to compare the efficacy and safety of Omapatrilat against enalapril in the treatment of hypertension [374909]. The OCTAVE trial was expected to generate data by mid-2001, which could allow for a launch by early 2002 [380280]. Phase III trials for hypertension had commenced by January 1998 [273646]. In January 2001, Merrill Lynch expected BMS to refile its NDA with the FDA in the second half of 2001 [395423]. In February 2001, Credit Suisse First Boston made a similar prediction, adding that it believed BMS would launch the drug in late 2002 or early 2003. The analysts also predicted peak sales for the drug of $585 million in 2005 [399484]. In May 2001, Merrill Lynch estimated sales of $1.8 billion in 2005 [411811].
Quantitative determination of BMS-186716, a thiol compound, in rat plasma by high-performance liquid chromatography-positive ion electrospray mass spectrometry after hydrolysis of the methyl acrylate adduct by the native esterases
J Chromatogr B Biomed Sci Appl 1997 Sep 26;698(1-2):123-32.PMID:9367200DOI:10.1016/s0378-4347(97)00292-2.
During method development in support of non-clinical studies in animal models, BMS-186716 was found to be extremely unstable in blood and plasma. Stabilization of the compound was achieved by reacting the compound with methyl acrylate (MA) in blood, from which the plasma was then prepared. While the resulting BMS-186716-MA adduct was found to be stable in dog plasma, and hence it was used as the basis for the method developed for analysis of dog plasma samples, the BMS-186716-MA adduct was found to be unstable in rat plasma as it was readily hydrolyzed to BMS-186716-acrylic acid (AA) by native esterases found in rat plasma. Although the finding of the instability of BMS-186716-MA in rat plasma was not the result of prospective planning, we were able to successfully develop a quantitative bioanalytical method using BMS-186716-AA as the analyte instead of the originally planned BMS-186716-MA analyte. The standard and quality-control (QC) samples were prepared by spiking blank plasma with BMS-186716-MA, and then allowing them to stand at room temperature for 1 h to convert BMS-186716-MA to BMS-186716-AA. After adding the internal standard BMS-188035-AA, each sample was acidified with HCl and then extracted with methyl tert.-butyl ether. The reconstituted extract was injected into a HPLC-electrospray ionization mass spectrometric system for detection by positive ion electrospray ionization. A lower limit of quantitation (LLQ) of 5 ng/ml was achieved, using 0.1 ml plasma and a standard curve range of 5-5000 ng/ml.