LCZ696A first in class ARNi (angiotensin receptor neprilysin inhibitor) CAS# 936623-90-4 |
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| Cas No. | 936623-90-4 | SDF | Download SDF |
| PubChem ID | 24755604 | Appearance | Powder |
| Formula | C48H57N6Na3O9 | M.Wt | 931 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Valsartan/sacubitril | ||
| Solubility | DMSO : ≥ 100 mg/mL (104.39 mM) H2O : ≥ 50 mg/mL (52.19 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | sodium (S)-5-(4'-((N-(1-carboxylato-2-methylpropyl)pentanamido)methyl)-[1,1'-biphenyl]-2-yl)tetrazol-1-ide 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate hydrate | ||
| SMILES | CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NN=N[N-]3)C(C(C)C)C(=O)[O-].CCOC(=O)C(C)CC(CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)[O-].O.[Na+].[Na+].[Na+] | ||
| Standard InChIKey | UOLUPHRXIRFONO-JOYYXRJNSA-K | ||
| Standard InChI | InChI=1S/C24H29N5O3.C24H29NO5.3Na.H2O/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23;1-3-30-24(29)17(2)15-21(25-22(26)13-14-23(27)28)16-18-9-11-20(12-10-18)19-7-5-4-6-8-19;;;;/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H2,25,26,27,28,31,32);4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28);;;;1H2/q;;3*+1;/p-3/t22-;17-,21+;;;;/m01..../s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | LCZ696 is a dual angiotensin II receptor and neprilysin inhibitor.In Vitro:LCZ696 is a single molecule that is comprised of molecular moieties of valsartan, an ARB, and AHU377, a neprilysin inhibitor (1:1 ratio)[1].In Vivo:LCZ696 exerts a blood pressure lowering effect. Blood pressure reduction by LCZ696 is associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. LCZ696 significantly ameliorates cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan[1]. The neprilysin inhibitor component of LCZ696, LBQ657, inhibits hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibits both hypertrophy and fibrosis. Dual valsartan+LBQ augment the inhibitory effects of valsartan and the highest doses completely abrogate angiotensin II-mediated effects[2]. Pre-treatment with LCZ696 reduces the ischemic area. The decrease in cerebral blood flow in the peripheral region of the ischemic area is significantly attenuated by pre-treatment with LCZ696. LCZ696 pre-treatment significantly decreases the increase of superoxide anion production in the cortex on the ischemic side[3]. References: | |||||
LCZ696 Dilution Calculator
LCZ696 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.0741 mL | 5.3706 mL | 10.7411 mL | 21.4823 mL | 26.8528 mL |
| 5 mM | 0.2148 mL | 1.0741 mL | 2.1482 mL | 4.2965 mL | 5.3706 mL |
| 10 mM | 0.1074 mL | 0.5371 mL | 1.0741 mL | 2.1482 mL | 2.6853 mL |
| 50 mM | 0.0215 mL | 0.1074 mL | 0.2148 mL | 0.4296 mL | 0.5371 mL |
| 100 mM | 0.0107 mL | 0.0537 mL | 0.1074 mL | 0.2148 mL | 0.2685 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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LCZ696 is a first in class ARNi (angiotensin receptor neprilysin inhibitor) comprising anionic moieties of AR valsartan and the neprilysin inhibitor prodrug AHU377 (1:1 ratio) for heart failure and hypertension.
The angiotensin receptors are G-protein-coupled receptors. They mediate the cardiovascular and other effects of angiotensin II which is a bioactive peptide of the renin–angiotensin system. Neprilysin is a neutral endopeptidase that degrades endogenous vasoactive peptides such as natriuretic peptides. Inhibition of neprilysin increases the natriuretic peptides concentration that contributed to cardiac, vascular and renal protection. [1]
In Sprague-Dawley rats, oral administration of LCZ696 led to a dose-dependent rise in immunoreactivity of atrial natriuretic peptide resulting from neprilysin inhibition. In hypertensive double transgenic rats, LCZ696 caused a dose-dependent and sustained reduction in mean arterial pressure. A healthy participants, a randomized, double-blind, placebo-controlled study confirmed that LCZ696 provided concurrent neprilysin inhibition and AT1 receptor blockade. LCZ696 was safe and well tolerated in human. [2] [3]
References:
McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
Gu J, Noe A, Chandra P, Al-Fayoumi S et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010 Apr;50(4):401-14.
Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure, Drug Discov Today: Ther Strategies (2014),
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Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.[Pubmed:28158398]
Eur Heart J. 2017 Apr 14;38(15):1132-1143.
Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and >/=140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP >/=140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.
Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study.[Pubmed:28338503]
J Cardiovasc Pharmacol. 2017 Jun;69(6):374-381.
We compared the systolic blood pressure (SBP)-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office SBP 150-179 mm Hg). Primary-dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24-hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily (1) is superior to valsartan 320 mg daily for lowering SBP, (2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, (3) represents the optimal dosage for systolic hypertension in patients of any age, and (4) is safe and well tolerated.
Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.[Pubmed:28089685]
J Pharm Sci. 2017 May;106(5):1439-1451.
Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.
Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy.[Pubmed:28030431]
J Hypertens. 2017 Apr;35(4):877-885.
OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of sacubitril/valsartan (LCZ696, an angiotensin receptor and neprilysin inhibitor) add-on to amlodipine compared with amlodipine monotherapy in Asian patients with systolic hypertension uncontrolled with amlodipine. METHODS: Patients with mean clinic SBP at least 145 mmHg and less than 180 mmHg after a 4-week treatment with amlodipine 5 mg/day were randomized to receive LCZ696/amlodipine (200/5 mg/day) or amlodipine 5 mg/day for 8 weeks. The primary assessment was the superiority of LCZ696/amlodipine versus amlodipine in lowering 24-h ambulatory SBP from baseline to week 8. Secondary assessments included 24-h ambulatory DBP and pulse pressure (PP), daytime and night-time BP, clinic BP and PP, BP control/responder rate (<140/90 mmHg or a reduction >/=20/10 mmHg from baseline), and safety. RESULTS: Of the 371 patients screened, 266 (71.7%) patients (mean age 55.4 years; 24-h SBP/DBP 139.0/86.1 mmHg at baseline) who did not respond to 4-week treatment with amlodipine 5 mg/day were randomized. At week 8, LCZ696/amlodipine provided greater reductions in 24-h SBP compared with amlodipine monotherapy from baseline (-13.9 versus -0.8 mmHg, P < 0.001). All the secondary efficacy assessments were significantly (P < 0.001) in favour of LCZ696/amlodipine, for instance, 24-h PP (-5.8 versus -0.6 mmHg). Overall, the incidence of adverse events was 20.0% with LCZ696/amlodipine and 21.3% with amlodipine. CONCLUSION: LCZ696/amlodipine showed significantly greater 24-h ambulatory BP and PP reductions compared with amlodipine monotherapy. Both treatments were generally well tolerated. Therefore, LCZ696/amlodipine combination could be an effective treatment for patients with systolic hypertension uncontrolled with amlodipine.
