| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg | |||
| 50mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
Ki: 0.45 nM (NEP), 0.64 nM (ACE)[1]; IC50: 8 nM (NEP), 5 nM (ACE)[2]
Omapatrilat targets two metalloproteases: angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP, also known as neprilysin). ACE is responsible for converting angiotensin I to the vasoconstrictor angiotensin II, while NEP degrades vasodilatory natriuretic peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Omapatrilat binds to both enzymes with high affinity, with Ki values of 0.64 nM for ACE and 0.45 nM for NEP. This dual inhibition produces vasodilation through both reduced angiotensin II production (via ACE inhibition) and increased natriuretic peptide levels (via NEP inhibition). |
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| ln Vitro |
Omapatrilat (Ki=0.45, 25, 0.64, 250 nM) shows poor action against ECE1, but significant potency for NEP, NEP2, and ACE, as well as moderately strong activity against APP [1]. Simpatril (10 mg/kg) produces rapid and potent suppression of renal NEP and ACE for 24 hours, respectively, according to in vitro autoradiography utilizing the particular radioligands for NEP and ACE inhibitors, 125I-RB104 and 125I-MK351A, respectively[4].
In vitro, Omapatrilat demonstrates potent inhibition of both ACE and NEP with low nanomolar Ki values (0.64 nM for ACE, 0.45 nM for NEP). The compound shows high selectivity for these two metalloproteases over other related enzymes. Enzyme kinetic studies confirm that Omapatrilat acts as a competitive inhibitor of both ACE and NEP. In cellular systems, the compound's dual inhibition leads to reduced angiotensin II production and increased natriuretic peptide levels, resulting in decreased vasoconstriction, reduced aldosterone secretion, and enhanced natriuresis. These in vitro findings established Omapatrilat as a prototypical vasopeptidase inhibitor. |
| ln Vivo |
In numerous animal models with varying degrees of plasma renin activity, omapatrilat exhibits excellent blood pressure decrease. In a test using cynomolgus monkeys, it also dramatically increases urine sodium, ANP, and cGMP excretion. Between 10 and 24 hours, omapatrilat lowers mean arterial pressure (MAP) by around 40 mmHg below baseline. On day three, the systolic blood pressure is 38 mmHg lower when oral omapatrilat at 100 μM/kg is administered once daily as opposed to vehicle [2]. Omapatrilat is frequently utilized in experimental procedures pertaining to heart failure and hypertension. Omapatrilat, when taken orally over time, has been shown to improve endothelium independent vasorelaxation to ANP and decrease aortic leakiness and atheroma formation[3]. In rats, omapatrilat significantly reduces plasma ACE and increases plasma renin activity[4].
In vivo, Omapatrilat produces significant antihypertensive effects in animal models and human subjects. In rat models, Omapatrilat reduces mean arterial pressure (MAP) approximately 40 mmHg below baseline from 10 to 24 hours after administration. The compound's dual mechanism provides more complete blood pressure control than ACE inhibition alone, as NEP inhibition prevents the degradation of natriuretic peptides that contribute to vasodilation and sodium excretion. Omapatrilat has been studied in clinical trials for hypertension and heart failure, showing efficacy in reducing blood pressure and improving hemodynamic parameters. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Omapatrilat measure inhibition of ACE and NEP activities using purified enzymes and fluorogenic or chromogenic substrates. For ACE inhibition, assays use the substrate hippuryl-histidyl-leucine (HHL), and the reaction product is quantified by fluorescence after derivatization or by HPLC. For NEP inhibition, assays use the substrate glutaryl-Ala-Ala-Phe-2-naphthylamide, and the released 2-naphthylamine is measured fluorometrically. IC50 and Ki values are determined from dose-response curves. Selectivity profiling against other metalloproteases (e.g., endothelin-converting enzyme, matrix metalloproteinases) confirms target specificity. Binding kinetics (kon, koff) may be assessed by SPR.
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| Cell Assay |
In vitro cellular assays for Omapatrilat are performed in cell lines expressing ACE and/or NEP to assess functional inhibition of enzyme activity. Cells are treated with Omapatrilat, and the conversion of angiotensin I to angiotensin II (ACE activity) or the degradation of natriuretic peptides (NEP activity) is measured by ELISA or LC-MS/MS. The compound's effects on downstream signaling pathways including the renin-angiotensin-aldosterone system and natriuretic peptide signaling can be assessed by measuring changes in gene expression (e.g., aldosterone synthase, BNP) or second messenger levels (e.g., cGMP for natriuretic peptide signaling).
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| Animal Protocol |
In vivo animal studies with Omapatrilat are conducted in rodent models of hypertension (spontaneously hypertensive rats, DOCA-salt hypertensive rats) and heart failure. Animals receive Omapatrilat via oral gavage at various doses, and blood pressure is measured by tail-cuff or telemetry. Hemodynamic parameters including cardiac output, stroke volume, and vascular resistance are assessed. Natriuretic peptide levels, plasma renin activity, angiotensin II levels, and aldosterone levels are measured to confirm target engagement. Renal function (glomerular filtration rate, sodium excretion) is evaluated in metabolic cage studies. Efficacy in heart failure models is assessed by echocardiography and survival analysis.
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Omatrara has an absolute oral bioavailability of 20% to 30%, and its absorption is not affected by food intake. Metabolism/Metabolites Liver Omapatrilat is orally bioavailable with good absorption and a favorable pharmacokinetic profile in preclinical and clinical studies. Following oral administration, the compound achieves therapeutic plasma concentrations with a half-life suitable for once- or twice-daily dosing. Omapatrilat is metabolized in the liver, and its metabolites are excreted primarily via the kidneys. The compound's dual mechanism provides sustained blood pressure reduction throughout the dosing interval. Detailed PK parameters including Cmax, Tmax, AUC, bioavailability, and half-life have been characterized in multiple species and in human clinical trials. |
| Toxicity/Toxicokinetics |
Omapatrilat was evaluated in extensive preclinical and clinical toxicology studies. While the compound demonstrated efficacy in reducing blood pressure in clinical trials, development was ultimately discontinued due to a higher incidence of angioedema compared to ACE inhibitor monotherapy. Angioedema is a known class effect of ACE inhibitors, and the combination of ACE and NEP inhibition may increase bradykinin levels to a greater extent than ACE inhibition alone, contributing to the elevated risk. Preclinical toxicology studies assessed acute and repeat-dose toxicity, genotoxicity, reproductive toxicity, and carcinogenicity. The compound's safety profile in animals was generally acceptable at therapeutic doses, but the clinical safety concern led to termination of development.
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| References |
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| Additional Infomation |
Omapatrilat is a dipeptide. Omatrala is an investigational drug that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). Inhibition of NEP increases natriuretic peptide levels, increases urinary sodium excretion, dilates blood vessels, and reduces preload and ventricular remodeling. Due to concerns about angioedema, this drug has not been approved by the FDA. Omatrala is an angiopeptidase inhibitor with antihypertensive activity. Omatrala works by inhibiting angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibition inhibits the renin-angiotensin-aldosterone system, thereby reducing vasoconstriction. Inhibition of neutral endopeptidase (NEP) inhibits the hydrolysis of various endogenous vasoactive peptides, such as bradykinin and substance P. Since NEP is the main enzyme that degrades natriuretic peptides, NEP inhibition also leads to an increase in natriuretic peptide cycling. Ultimately, both effects result in vasodilation. Drug Indications Omatricilla is used to treat hypertension. Mechanism of Action Omatricilla binds to angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). This leads to a decrease in the production of the renin-angiotensin-aldosterone system and an increase in the natriuretic peptidase cycle. Pharmacodynamics Omatricilla is used to treat hypertension. It is an angiopeptidase inhibitor that simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Omatricilla lowers blood pressure by inhibiting the activity of angiotensin-converting enzyme (ACE), which causes vasoconstriction. However, unlike other drugs, omatricilla also inhibits another enzyme called neutral endopeptidase (NEP), which helps in vasodilation. In patients with salt-sensitive hypertension who typically do not respond well to ACE inhibitors, omatricilla is more effective than the ACE inhibitor lisinopril.
Omapatrilat (BMS-186716) is a potent, orally active dual inhibitor of ACE and NEP, representing the vasopeptidase inhibitor class. It was developed for hypertension and heart failure. Its Ki values are 0.64 nM for ACE and 0.45 nM for NEP. Clinical development was discontinued due to angioedema risk. The compound remains a valuable research tool for studying the combined inhibition of the renin-angiotensin system and natriuretic peptide degradation. No regulatory approvals have been granted. |
| Molecular Formula |
C19H24N2O4S2
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|---|---|
| Molecular Weight |
408.53486
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| Exact Mass |
408.117
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| Elemental Analysis |
C, 55.86; H, 5.92; N, 6.86; O, 15.67; S, 15.70
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| CAS # |
167305-00-2
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| PubChem CID |
656629
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| Appearance |
White to gray solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
724.2±60.0 °C at 760 mmHg
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| Flash Point |
391.8±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.645
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| LogP |
1.65
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
568
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O=C([C@@H]1CCC[C@](N21)([H])SCC[C@H](NC([C@@H](S)CC3=CC=CC=C3)=O)C2=O)O
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| InChi Key |
LVRLSYPNFFBYCZ-VGWMRTNUSA-N
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| InChi Code |
InChI=1S/C19H24N2O4S2/c22-17(15(26)11-12-5-2-1-3-6-12)20-13-9-10-27-16-8-4-7-14(19(24)25)21(16)18(13)23/h1-3,5-6,13-16,26H,4,7-11H2,(H,20,22)(H,24,25)/t13-,14-,15-,16-/m0/s1
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| Chemical Name |
(4S,7S,10aS)-4-((S)-2-mercapto-3-phenylpropanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid
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| Synonyms |
BMS 186716; Vanlev; Omapatrilat; 167305-00-2; BMS-186,716; Vanlev; Omapatrilate; BMS186716; BMS-186716;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 31 mg/mL (~75.88 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.25 mg/mL (10.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 42.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4478 mL | 12.2390 mL | 24.4780 mL | |
| 5 mM | 0.4896 mL | 2.4478 mL | 4.8956 mL | |
| 10 mM | 0.2448 mL | 1.2239 mL | 2.4478 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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