Future drug discovery in renin-angiotensin-aldosterone system intervention

ABSTRACT

Introduction: Renin-angiotensin-aldosterone system inhibitors (RAASIs), including angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases.

Areas covered: The authors searched MEDLINE, PubMed and ClinicalTrials.gov to identify eligible full-text English language papers. Herein, the authors discuss AT2-receptor agonists and ACE2/angiotensin-(1–7)/Mas-receptor axis modulators, direct renin inhibitors, brain aminopeptidase A inhibitors, biased AT1R blockers, chymase inhibitors, multitargeted drugs, vaccines and aldosterone receptor antagonists as well as aldosterone synthase inhibitors.

Expert opinion: Preclinical studies have demonstrated that activation of the protective axis of the RAAS represents a novel therapeutic strategy for treating cardiovascular and renal diseases, but there are no clinical trials supporting our expectations. Non-steroidal MRAs might become the third-generation of MRAs for the treatment of heart failure, diabetes mellitus and chronic kidney disease. The main challenge for these new drugs is that conventional RAASIs are safe, effective and cheap generics. Thus, the future of new RAASIs will be directed by economical/strategic reasons.

KEYWORDS:

• Renin-angiotensin-aldosterone system
• ACE2
• angiotensin-(1-7)
• aminopeptidase A inhibitors
• mineralocorticoid receptor antagonists

Article highlights

• Conventional renin-angiotensin-aldosterone system inhibitors (RAASIs), i.e. angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases. However, residual risk for cardiovascular events or progression of established cardiovascular diseases remains significantly high in patients treated with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin AT1 receptor blockers (ARBs).

• In recent years, a ‘protective axis’ of the RAAS that opposes many of the AT1 receptor-mediated actions was described and new therapeutic targets, including AT2 receptor agonists, activators of the ACE2/Ang-(1-7)/MasR axis and combined angiotensin receptor modulation, were identified. Additionally, the identification of the Ang-(1-12)/chymase II axis, an alternative noncanonical renin-independent pathway for Ang II formation, adds further complexity and increases our knowledge of the RAAS.

• Vaccines, direct renin inhibitors, biased AT1 receptor blockers, centrally acting aminopeptidase A inhibitors, chymase inhibitors and multitargeted drugs remain as possible alternative RAASIs.

• Multiple putative clinical indications have been proposed for the new RAASIs based on preclinical studies. However, at the present time, their ‘real clinical’ efficacy and safety remains uncertain, because there are no clinical data confirming the preclinical evidence.

• New non-steroidal MRAs with higher selectivity, greater binding affinity and a novel mechanism of action are under clinical development, while aldosterone synthase inhibitors have been relegated to the treatment of Cushing’s disease.

• The ambitious clinical development program of finerenone and the promising results observed in phase II clinical trials in patients with heart failure, chronic kidney disease and diabetic nephropathy suggest that third-generation MRAs may be a reality in the near future.

• The main challenge for these new RAASIs will be to demonstrate that they are as effective and safe (or better tolerated than) than conventional RAASIs which, at the present time, are effective, safe and cheap generics for the treatment of cardiovascular and renal disorders.

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Acknowledgment

We thank Paloma Vaquero for her invaluable technical assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the European Regional Development Fund (FEDER) and grants from the Institute of Health Carlos III (PI16/00398 and CB16/11/00303) as well as the BBVA Foundation.