AHU-377 hemicalcium salt

AHU-377 hemicalcium salt is angiotensin receptor neprilysin inhibitor being studied for use in combination with valsartan for heart failure. Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases. LBQ657 inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.

Product information

CAS Number: 1369773-39-6

Molecular Weight: 861.04

Formula: C48H56CaN2O10

Synonym:

CZ 696

Related CAS Number:

149709-62-6 (free acid)

149690-05-1 (sodium)

Chemical Name: Calcium 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate

Smiles: [Ca+2].C[C@H](C[C@@H](CC1C=CC(=CC=1)C1C=CC=CC=1)NC(=O)CCC([O-])=O)C(=O)OCC.C[C@H](C[C@@H](CC1C=CC(=CC=1)C1C=CC=CC=1)NC(=O)CCC([O-])=O)C(=O)OCC

InChiKey: DDLCKLBRBPYKQS-OXXXZDCLSA-L

InChi: InChI=1S/2C24H29NO5.Ca/c2*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;/h2*4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28);/q;;+2/p-2/t2*17-,21+;/m11./s1

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO (10 mg/mL) and in ethanol (5mg/mL).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

Sacubitril (AHU-377) is a single molecule that is comprised of molecular moieties of valsartan, an ARB, and Sacubitril hemicalcium salt, a neprilysin inhibitor (1:1 ratio). Sacubitril (AHU-377) is converted by enzymatic cleavage of the ethyl ester into the active neprilysin inhibiting metabolite LBQ657. The inactive NEPi precursor, Sacubitril hemicalcium salt, does not inhibit collagen accumulation in fibroblasts nor cardiac myocyte hypertrophy. In cardiac fibroblasts, the active NEPi LBQ657 had no discernible effects. In contrast, LBQ657 modestly inhibits cardiac myocyte hypertrophy.

In Vivo:

In humans, Sacubitril (AHU-377)(tmax 0.5-1.1 h) are absorbed quickly. Sacubitril hemicalcium salt is converted rapidly into LBQ657 with its tmax being reached in 1.9-3.5 h. Mean t1/2 values for the biologically active LBQ657 is 9.9-11.1 h.In vehicle-treated dogs, ANF increases urinary sodium excretion from 17.3±3.6 to 199.5±18.4 pequivkglmin. This effect is potentiated significantly in animals which receive Sacubitril (AHU-377). Urinary volume is also potentiated in animals which receive an iv administration of Sacubitril (AHU-377).

References:

1. Fabris E, Merlo M, Rapezzi C, Ferrari R, Metra M, Frigerio M, Sinagra G. Sacubitril/Valsartan: Updates and Clinical Evidence for a Disease-Modifying Approach. Drugs. 2019 Sep;79(14):1543-1556. doi: 10.1007/s40265-019-01181-2. Review. PubMed PMID: 31432436.
2. Dewan P, Docherty KF, McMurray JJV. Sacubitril/Valsartan in Asian Patients with Heart Failure with Reduced Ejection Fraction. Korean Circ J. 2019 Jun;49(6):469-484. doi: 10.4070/kcj.2019.0136. Review. PubMed PMID: 31172710; PubMed Central PMCID: PMC6554586.
3. De Vecchis R, Ariano C. Vasodilatory Properties of Sacubitril/Valsartan Explored in Hypertensives Aged Over 55 Years: A Meta-Analysis. High Blood Press Cardiovasc Prev. 2019 Apr 1. doi: 10.1007/s40292-019-00313-9. [Epub ahead of print] Review. PubMed PMID: 30937854.
4. Fonseca C, Brito D, Ferreira J, Franco F, Morais J, Silva Cardoso J; Experts opinion, endorsed by the Working Group on Heart Failure of the Portuguese Society of cardiology. Sacubitril/valsartan: A practical guide. Rev Port Cardiol. 2019 May;38(5):309-313. doi: 10.1016/j.repc.2018.10.008. Epub 2019 Jan 22. Review. English, Portuguese. PubMed PMID: 30679005.
5. Sauer AJ, Cole R, Jensen BC, Pal J, Sharma N, Yehya A, Vader J. Practical guidance on the use of sacubitril/valsartan for heart failure. Heart Fail Rev. 2019 Mar;24(2):167-176. doi: 10.1007/s10741-018-9757-1. Review. PubMed PMID: 30565021; PubMed Central PMCID: PMC6394573.

Products are for research use only. Not for human use.