Spotlight on valsartan–sacubitril fixed-dose combination for heart failure: the evidence to date

Abstract

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin–angiotensin–aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Pharmacoeconomic Analysis of Chronic Heart Failure Drug Therapy in Patients With Comorbid Conditions

“…Препарат обладает новым механизмом действия, связанным с одновременным блокированием рецепторов ангиотензина II 1-го типа валсартаном и ингибированием активности неприлизина за счет активного метаболита сакубитрила (вещество LBQ657). Данные эффекты являются взаимодопол-няющими, одновременно обеспечиваются увеличение уровня натрийуретических и других вазоактивных пептидов (обычно расщепляемых неприлизиом) и подавление ренин-ангиотензин-альдостероновой системы [13]. Данный препарат хорошо зарекомендовал себя в ходе обширного РКИ PARADIGM-HF [14][15][16] в рамках терапии ХСН со сниженной фракцией выброса, показав при этом интересные результаты у пациентов с сахарным диабетом (СД) 2 типа.…”

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

“…Among the different medication options for the treatment of hypertension and related cardiovascular complaints [1], drugs affecting the renin-angiotensin-aldosterone system have proved to be highly effective [1]. One prominent representative of this class of agents is LCZ696 (Novartis International AG, Basel, Switzerland), which was approved by the FDA in 2015 for the treatment of heart failure in patients with reduced ejection fraction [2]. The fixed-dose combination drug marketed under the brand name Entresto® comprises the active pharmaceutical ingredient (API) valsartan, an angiotensin IIreceptor antagonist, and the prodrug sacubitril 1 [3].…”

“…The fixed-dose combination drug marketed under the brand name Entresto® comprises the active pharmaceutical ingredient (API) valsartan, an angiotensin IIreceptor antagonist, and the prodrug sacubitril 1 [3]. The latter compound is metabolized in the body to an active neprilysin inhibitor upon cleavage of its ethyl ester moiety [2]. The synthesis of sacubitril 1 was first reported by Ksander et al [4] in 1995, starting from an unnatural D-amino acid derivative 3.…”

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

“…In this work an outlook on the planned realisation of the integrated multistep continuous flow synthesis of valsartan and sacubitril within the frame of the ONE-FLOW project is given. The compounds are well known as APIs in a combination drug for the treatment of hypertension and chronic heart failure (Entresto ® , Novartis) [ 31 – 35 ]. A preliminary scheme of the planned synthetic route is shown in Fig.…”