149709-62-6

Basic information

• Product Name: AHU-377
• Synonyms: AHU-377;4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid;4-(((2R,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid;(2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester;(2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-(3-carboxypropanamido)-2-methylpentanoic acid;4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid;4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid;AHU-77
• CAS NO: 149709-62-6
• Molecular Formula: C₂₄H₂₉NO₅
• Molecular Weight: 411.49
• EINECS: 1592732-453-0
• Product Categories: LCZ696;intermediates;Sacubitril;LCZ 696
• Mol File: 149709-62-6.mol
• Article Data: 35

Chemical Properties

• Boiling Point: 656.9±55.0 °C(Predicted)
• Appearance: /
• Density: 1.151±0.06 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: ≥41.1 mg/mL in DMSO; ≥21.45 mg/mL in H2O with ultrasonic; ≥26.85 mg/mL in EtOH with ultrasonic
• PKA: 4.72±0.10(Predicted)
• CAS DataBase Reference: AHU-377(CAS DataBase Reference)
• NIST Chemistry Reference: AHU-377(149709-62-6)
• EPA Substance Registry System: AHU-377(149709-62-6)

Safety Data

• Hazardous Substances Data: 149709-62-6(Hazardous Substances Data)

Usage

Pharmacologic action

AHU377 and angiotensin IIAT1 receptor antagonist valsartan at a molar ratio of 1: 1 compose LCZ696. LCZ696 was a dual inhibitor of angiotensin II (AT2) receptor and enkephalinase (Neprilysin) receptor. And with its better antihypertensive efficacy than standard antihypertensive drugs, it is a new drug for the treatment of heart failure. AHU377 is a prodrug that converts the active form of the enzyme cleavage LBQ657 ethyl ester. So far its efficacy and safety in milestone phase III surpass the clinical standard drug enalapril. In a clinical trial of the drug, 100 to 400 mg of combined drugs, 80 to 320 mg of valsartan, 200 mg of neprilysin inhibition or placebo were given to the patients in the double-blind trial of phase two with mild to moderate hypertension. The combined drugs are more effective and better tolerated with no vascular edema report than solely applied valsartan or other drugs. LCZ696 shows sustainable treatment benefits in the early treatment: (1) a 20% reduction in the risk of death from cardiovascular disease (p = 0.00004). (2) hospitalization for heart failure was reduced by 21% (p = 0.00004). (3) all-cause mortality was reduced by 16% (p = 0.0005). (4) The overall risk is reduced by 20% according to the composite measure of the primary endpoint of hospitalization for cardiovascular death or heart failure (p = 0.0000002).

Novartis’ New Angiomyocardiac LCZ696

According to a recent study published by Novartis, LCZ696, a cardiovascular drug being developed by the company, will become a new hope for the company. The current study shows that this drug functions well in the remission of cardiovascular necrosis and other symptoms caused by heart disease. LCZ696 is a combination of Novartis Diovan and AHU-377. Some analysts have spoken highly of the drug and estimated that it might be submitted to the FDA as early as next year. Once confirmed in the audit it will mark another great step forward of Novartis in the field of cardiovascular drugs. Although it showed high expectations to LCZ696, Novartis still has a long way to go, given the setbacks of its serelaxin in the FDA and the European Medicines Administration. The news came straight from Basel as investigators around the world were wrapping up the big scientific meeting of the American College of Cardiology.

Market analysis

In the field of research and development of drugs, most of the success of the new drugs in phase II will always lead to a series of competitor projects. The LCZ696 performs so prominently that the industry was shocked. It is predicted that few cardiovascular drugs will be qualified to compete with the LCZ696 in the next few years. Some analysts predict that the LCZ696 sales will peak at $ 8 billion, while Deutsche Bank analysts expect the drug to peak at $ 6 billion, given LCZ696's superior performance in reducing cardiovascular risk. Although the data are slightly different, there is no doubt that, LCZ696 will become a super star to lead the cardiovascular treatment to step into a new era.

Biological Activity

ahu-377 is an inhibitor of neprilysin with ic50 value of 5nm [1].ahu-377 and the angiotensin ii at1 receptor antagonist valsartan compose lcz696 in a 1:1 molar ratio. lcz696 is an angiotensin receptor neprilysin inhibitor. it can reduce blood pressure and may be a novel drug for the treatment of heart failure. ahu-377 is a prodrug, it can be converted by enzymatic cleavage of the ethyl ester into the active form lbq657. it is reported that ahu-377(30 and 100 mg/kg, po) can cause antihypertensive effect in a dose-dependent manner in dahl-ss rats. but in the doca-salt hypertensive rats, it shows a weak reduction [2, 3].

references

[1] ksander gm, ghai rd, dejesus r, diefenbacher cg, yuan a, berry c, sakane y, trapani a. dicarboxylic acid dipeptide neutral endopeptidase inhibitors. j med chem. 1995 may 12;38(10):1689-700.[2] voors aa, dorhout b, van der meer p. the potential role of valsartan + ahu377 ( lcz696 ) in the treatment of heart failure. expert opin investig drugs. 2013 aug;22(8):1041-7. [3] laxminarayan g hegde, cecile yu, cheruvu madhavi et al. comparative efficacy of ahu-377, a potent neprilysin inhibitor, in two rat models of volume-dependent hypertension. bmc pharmacology 2011, 11(suppl 1):p33.

Upstream product

• 1012341-48-8 (2E,4R)-5-{[1,1'-biphenyl]-4-yl}-4-{[(tert-butoxy)carbonyl]amino}-2-methylpent-2-enoic acid 
• 92-66-0 4-bromo-1,1'-biphenyl 
• 108-30-5 succinic acid anhydride 
• 1039307-95-3 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid 
• 64-17-5 ethanol 
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• 1573000-28-8 (S)-1-([1,1’-biphenyl]-4-yl)-3-chloropropan-2-ol 
• 1038924-97-8 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methyl pentanoate 

Downstream Products

• 149690-05-1 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate monosodium salt 
• 936623-90-4 trisodium [3-((1S,3R)-1-biphenyl-4-yl-methyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3’-methyl-2’-(pentanoyl{2”-(tetrazol-5-ylate)biphenyl-4’-yl-methyl}amino)butyrate] hemipentahydrate 

Relevant articles and documents

Preparation method of

The preparation method comprises the following steps 1-11: Wherein. ROH (Formula X) is a chiral alcohol and the like, PG is a hydroxy protecting group, a compound of Formula VI and a compound of Formula V are the chiral auxiliary of the present invention. To the invention, the chiral auxiliary base ROH compound and the chiral alcohol X (Formula VI) are used for preparing the chiral auxiliary base-type compound of formula V IV and the compound of Formula XI, and the compound of formula IV can be prepared through three-step simple operation steps of chiral auxiliary base. Be applicable to industrial production.

Preparation method of key component sacubitril of novel anti-heart-failure drug Entresto

The invention relates to a preparation method of a key component sacubitril of a novel anti-heart-failure drug Entresto. The chemical name of sacubitril is 4-(((2S,4R)-1-(1,1'-biphen-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) amino)-4-oxobutyric acid. According to the method, 4-bromobiphenyl is used as an initial raw material, and the method is simple in process route, low in cost and suitable forindustrial production.

AMMONIUM CARBOXYLATE COMPOUND, CRYSTALLINE FORM, AMORPHOUS FORM AND PREPARATION METHOD THEREOF

The present disclosure belongs to the field of chemical synthesis, and in particular relates to an ammonium carboxylate compound, a crystalline form and an amorphous form, and a preparation method thereof. The present disclosure prepares the compound and the crystalline form I and its single crystal, amorphous form and crystalline form II thereof. The compound, the crystalline forms, the single crystal and the amorphous form can stably exist and exhibit good solid forms, suitable for medicine-making. Furthermore, these products possess high purity and less single impurity. Moreover, the preparation methods of the present disclosure are easy to implement due to the simple processes with mild reaction conditions, and could produce products of high yield and high purity without complex purification steps. Furthermore, the preparation methods may facilitate safety, environmental protection, and industrial production.