Key result
Aldosterone synthase inhibitors like BI 690517 must selectively inhibit mineralocorticoid receptors despite ~95% receptor homology.
Why the study?
Targeting aldosterone is critical in vascular disease, but new aldosterone synthase inhibitors need to selectively inhibit mineralocorticoid receptors while sparing glucocorticoid receptors despite high receptor homology.
Aldosterone synthase inhibitors like BI 690517 offer a novel approach to managing hypertension and heart failure, provided they can achieve high selectivity for the mineralocorticoid receptor.
Selectivity for mineralocorticoid over glucocorticoid receptors remains essential for aldosterone synthase inhibitors; leaves open clinical viability in hypertension and HF.
Aldosterone plays a critical role in maintaining volume and blood pressure control. It also plays a highly negative role in vascular diseases such as systemic hypertension, congestive heart failure, and cardiorenal syndrome due to the critical role that the renin-angiotensin-aldosterone system plays in these diseases from oxidative stress, vasoconstriction, and vascular remodeling caused by angiotensin II. Controlling aldosterone involves drugs such as angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and mineralocorticoid receptor antagonists (MRAs). Recent guidelines suggest that the MRAs were more beneficial than angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and diuretics in resistant hypertension. It is also essential to understand the role of both mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) because they are present in many of the same tissues, and the balance of these 2 receptors is critical for homeostasis. Glucocorticoids activate MRs at basal levels and GRs at stress levels. During oxidative stress, MR activation can negatively affect the balance of MRs/GRs interactions, cognition, and memory. The older drugs in this category were less effective than MRAs in controlling blood pressure. A new class of drugs to consider are the aldosterone synthase inhibitors, which inhibit salt and water reabsorption and decrease sympathetic stimulation. The ideal candidate drug must be capable of inhibiting the MR while sparing the glucocorticoid receptor, a challenge given the 95% homology of these receptors.
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Treihaft et al. (2025) conducted a review in Hypertension, congestive heart failure, and cardiorenal syndrome. Aldosterone synthase inhibitors (BI 690517) was evaluated. Aldosterone synthase inhibitors like BI 690517 must selectively inhibit mineralocorticoid receptors while sparing glucocorticoid receptors, a challenge given the 95% homology of these receptors.
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