Baxdrostat versus Osilodrostat: Steroid Biosynthesis in Human Adrenocortical Cells

To compare the functional selectivity of baxdrostat versus osilodrostat in primary human adrenocortical cells, focusing on aldosterone suppression while preserving cortisol biosynthesis, we conducted an experimental ex vivo study using primary cells derived from aldosterone-producing adenomas, cortisol-producing tumors, and normal adrenal cortex. Cells were stimulated with adrenocorticotropic hormone (10 nM) and exposed for 72 h to baxdrostat, osilodrostat, or metyrapone (0-10 μM). Outcomes included geometric mean (GM) IC50 values for aldosterone and cortisol, LC-MS/MS steroid profiling, and molecular docking to CYP11B2/CYP11B1. In aldosterone-producing adenoma cells, baxdrostat selectively inhibited aldosterone (GM IC50 = 0.041 μM) and did not achieve 50% cortisol suppression in cortisol-producing tumor or normal adrenal cortex within 0-10 μM. Osilodrostat inhibited aldosterone (GM IC50 = 0.0022 μM) and cortisol (GM IC50 = 0.196 μM). Steroid profiling showed a modest, selective rise in 11-deoxycorticosterone with baxdrostat (+3.76-fold), whereas osilodrostat produced larger increases in 11-deoxycorticosterone (+25.4-fold) together with androgen elevations. Docking supported the mechanism: baxdrostat showed stronger predicted binding to CYP11B2 (-11.5 kcal/mol) than osilodrostat (-8.7 kcal/mol) with limited engagement of CYP11B1. Baxdrostat demonstrated greater functional selectivity for CYP11B2, with minimal cortisol-axis impact and smaller upstream precursor accumulation than osilodrostat. These human-tissue data inform dose selection and safety monitoring strategies for selective aldosterone synthase inhibition in aldosterone-mediated and treatment-resistant hypertension.