selective aldosterone synthase inhibitors

Selective aldosterone synthase inhibitors (ASIs) are a class of small molecule therapeutics designed to potently and selectively inhibit the enzyme CYP11B2 (aldosterone synthase). This enzyme is responsible for the final steps of aldosterone biosynthesis in the adrenal gland. By lowering plasma aldosterone levels, ASIs provide a novel mechanism for treating hypertension, particularly in patients with resistant or uncontrolled high blood pressure where aldosterone excess is a primary driver. Unlike older mineralocorticoid receptor antagonists (MRAs), which block the receptor, ASIs reduce the production of the hormone itself. A key challenge in their development is achieving high selectivity for CYP11B2 over the closely related enzyme CYP11B1 (11β-hydroxylase), which is 93% identical and essential for cortisol synthesis. Leading clinical candidates in this class include lorundrostat and baxdrostat, which have demonstrated significant blood pressure reductions in clinical trials.