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Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin–Angiotensin–Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.

Congestive heart failure (CHF) is a systolic dysfunction of the heart in which the pumping efficiency or ejection fraction reduces and the body responses by compensatory mechanisms. Sympathetic activation and activating the RAAS help in the short run but are deleterious in the longer run and cause myocardial remodeling and apoptosis. Drugs which remove these stressors usually reduce mortality such as RAAS inhibitors, beta-blockers, mineralocorticoid antagonists and a combination of hydralazine and isosorbide dinitrate. Drugs which act to reduce congestion and other symptoms reduce preload (diuretics, nitrates) and afterload (RAAS inhibitors). Digoxin works uniquely by stimulating the heart but its use has come down because of its narrow therapeutic window and availability of better drugs. Newer agents include recombinant atrial natriuretic peptide and vasopeptidase inhibitors. Decompensated heart failure is treated by inotropic agents such as dopamine, dobutamine, and phosphodiesterase inhibitors.

Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 A, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.

The review presents data on the involvement of the system of circulating and renal tissue natriuretic peptides in the mechanism that supports water-salt homeostasis and protects the kidney from damage of various etiologies, as well as the results obtained in assessing the clinical efficacy and safety of a new drug from vasopeptidase inhibitors LCZ696 (sacubitryl/valsartan) in patients with chronic kidney disease.

A method of synthesis of 3-thiopropinyl derivatives of 5-oxo-1,3,4-benzothiadiazepine-4-acetic acid, potential antihypertensive drugs, vasopeptidase inhibitors, starting from 2-thiobenzoic acid hydrazide has been elaborated.

Previously we had shown that a vasopeptidase inhibitor, combination drug containing angiotensin converting enzyme and neprilysin inhibitors, was an effective treatment for diabetes vascular and neural complications. However, once in clinical trials, side effects prevented further development of this class of drugs. This lead to development of sacubitril/valsartan, combination drug similar to vasopeptidase inhibitors containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be also an effective treatment for diabetic peripheral neuropathy. Using a rat model of type 2 diabetes, early and late intervention protocols, 4 and 12 weeks post hyperglycemia, respectively, rats were treated daily by gavage with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural endpoints. The results demonstrated that efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the late intervention protocol, treatment of the diabetic rats was initiated well after the appearance of vascular and neural complications. Sacubitril/valsartan treatment was found to not only slow progression of vascular and neural deficits but also stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities and sensitivity/regeneration of sensory nerves of the skin and cornea. These studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy and since it already has FDA approval for treatment of heart failure advancing this drug to clinical trials could proceed quickly. Disclosure M.A. Yorek: None.

This article overviews the natriuretic peptides (NPs) system, its role and the development of NP-based treatment of heart failure (HF)., After its discovery in the early 1980s, the natriuretic peptide (NP) system has been extensively characterized and its potential influence in the development and progression of heart failure (HF) has been investigated. HF is a syndrome characterized by the activation of different neurohormonal systems, predominantly the renin–angiotensin (Ang)–aldosterone system (RAAS) and the sympathetic nervous system (SNS), but also the NP system. Pharmacological interventions have been developed to counteract the neuroendocrine dysregulation, through the down modulation of RAAS with ACE (Ang-converting enzyme) inhibitors, ARBs (Ang receptor blockers) and mineralcorticoid antagonists and of SNS with β-blockers. In the last years, growing attention has been paid to the NP system. In the present review, we have summarized the current knowledge on the NP system, focusing on its role in HF and we provide an overview of the pharmacological attempts to modulate NP in HF: from the negative results of the study with neprilysin (NEP) inhibitors, alone or associated with an ACE inhibitor and vasopeptidase inhibitors, to the most recently and extremely encouraging results obtained with the new pharmacological class of Ang receptor and NEP inhibitor, currently defined ARNI (Ang receptor NEP inhibitor). Indeed, this new class of drugs to manage HF, supported by the recent results and a vast clinical development programme, may prompt a conceptual shift in the treatment of HF, moving from the inhibition of RAAS and SNS to a more integrated target to rebalance neurohormonal dysregulation in HF.

The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, has emerged as an important diagnostic, prognostic, and therapeutic tool in patients with heart failure (HF). The rapid incorporation into clinical practice of bioassays to BNP concentrations and pharmacological agents that augment the biological actions of this peptide such as nesiritide or vasopeptidase inhibitors has shown the potential for translational research to improve patient care. Despite the indirect evidence in support of a potential benefit from raising BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily confer cardiovascular benefits in patient with HF. Moreover, in experimental HF, the response to treatments targeting specific natriuretic peptide receptors (NPRs) signaling seems to be attenuated. A better understanding of the NPRs signaling in HF would be clinically relevant and thus required, in order to devise strategies to develop novel agents and technologies that directly target this signaling pathway.

The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Neprilysin is acknowledged as a key player in neurohormonal regulation, a cornerstone of modern drug therapy in chronic heart failure. In the cardiovascular system, neprilysin cleaves numerous vasoactive peptides, some with mainly vasodilating effects (natriuretic peptides, adrenomedullin, bradykinin) and other with mainly vasoconstrictor effects (angiotensin I and II, endothelin-1). For decades, neprilysin has been an important biotarget. Academia and industry have combined active efforts to search for neprilysin inhibitors (NEPIs) that might be useful in clinical practice. NEPI monotherapy was initially tested with little success due to efficacy issues. Next, combination of NEPI and ACE-inhibiting activity agents were abandoned due to safety concerns. Recently, the combination of NEPI and ARB, also known as ARNI, has shown better than expected results in heart failure with reduced ejection fraction, and multitude of ongoing studies are set to prove its value across the heart failure spectrum.

Hypertension is the most common risk factor for cardiovascular disease, stroke, renal failure, and death. Recent drug monitoring studies found non-adherence to BP lowering therapy in 25% to 65% of patients with apparent treatment-resistant hypertension (TRH). This review focuses on the latest development of antihypertensive medication, such as vasopeptidase inhibitors, aldosterone synthase inhibitors, Soluble Epoxide Hydrolase Inhibitors, agonists of natriuretic peptide receptor, Vasoactive Intestinal Peptide Receptor Agonist, a novel mineralocorticoid receptor antagonist, inhibitors of aminopeptidase A, dopamine β-hydroxylase inhibitor, intestinal Na+/H+ exchanger 3 inhibitor and other agents.

A number of novel drugs are currently under development for cardiovascular disease prevention. We describe here the pharmacological properties of various pharmacological classes that can represent an important therapeutic advance. First, we analyze the novel molecules targeting isolated systolic hypertension, which represents the most common form of arterial aging. These include molecules that inhibit or break down advanced-glycation end products, molecules that target arterial calcification, and NO donors. Second, we analyze novel antihypertensive agents that include dual vasopeptidase inhibitors, aldosterone synthase inhibitors, and novel drugs targeting the renin-angiotensin system, such as angiotensin AT2-receptor agonists. Third, we discuss some alternatives to classical drugs, particularly telomerase inhibitors, drugs targeting Lamin A, and drugs targeting Khloto. In conclusion, we review novel agents targeting isolated systolic hypertension, which, despite the discovery of numerous pharmacological targets and promising results obtained in the preclinical stage, proved to have more difficulties and be less productive than expected in clinical development. However, continuing efforts should be put into the development of innovative pharmacological strategies because these novel drugs may represent an important therapeutic approach for treating other diseases such as diabetes, congestive heart failure, or chronic kidney disease, all of which represent forms of accelerated vascular aging.