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How Does Baxdrostat Affect Aldosterone Levels?
Figure 2. Figure 2. Aldosterone Synthesis in the Zona Glomerulosa.
In the zona glomerulosa of the adrenal gland, the CYP11B2 enzyme (also known as aldosterone synthase) catalyzes the synthesis of aldosterone. CYP11B2 and CYP11B1 (also known as 11β-hydroxylase, which synthesizes cortisol and is the final enzyme in the cortisol-synthesis pathway) share 93% sequence similarity, and drugs that block CYP11B2 have the potential to block CYP11B1.
Baxdrostat, a [small-molecule drug. opens in new tab][14] (see [Key Concepts][15]), decreases levels of aldosterone by inhibiting its synthesis. It does so by inhibiting the CYP11B2 enzyme (also known as aldosterone synthase) that catalyzes the final steps of aldosterone synthesis from cholesterol ([Figure 2][16]). Moreover, it is highly selective for CYP11B2. This selectivity is good because the CYP11B2 enzyme has 93% sequence similarity with CYP11B1 (also known as 11β-hydroxylase), the final enzyme in the cortisol-synthesis pathway. This high degree of similarity led to cross-reactivity and suppression of cortisol synthesis by earlier aldosterone synthase inhibitors, which rendered these compounds inappropriate as antihypertensive agents. Freeman et al. found that in addition to lowering plasma aldosterone levels and blood pressure, baxdrostat had no substantive effect on plasma cortisol levels.