Advancing antihypertensive drug development

Abstract

Hypertension affects more than a billion individuals worldwide and remains a major cause of cardiovascular morbidity and mortality. Despite advances in therapies, optimal blood pressure control remains elusive for many patients because of treatment resistance, adverse effects, and adherence challenges. This review highlights innovative approaches in hypertension management. Aldosterone synthase inhibitors (ASIs) and non-steroidal mineralocorticoid receptor antagonists improve blood pressure control and offer cardiorenal benefits while reducing adverse effects including hyperkalaemia. Endothelin receptor antagonists show promise in resistant hypertension by addressing vasoconstrictive pathways. RNA-based therapies, like zilebesiran, provide a novel approach to suppress angiotensinogen, offering durable antihypertensive effects with less frequent dosing. Additional advances include AT₂ receptor agonists, ACE2/Angiotensin-(1-7)/MAS receptor activators and NAD⁺ boosting compounds, which target key mechanisms of vascular dysfunction and ageing-related hypertension. Gut microbiome-targeted therapies and fixed-dose combination pills are also discussed for their potential to enhance blood pressure control and patient adherence. These emerging therapies not only aim to lower blood pressure but also address underlying pathophysiological mechanisms, offering a precision-focussed approach to treatment. By critically analysing these developments, this review provides insights into how novel strategies can overcome existing challenges in hypertension management, reduce the global disease burden and improve patient outcomes.

Keywords: endothelin receptor antagonists; hypertension; mineralocorticoid receptor antagonist.