Baxdrostat versus osilodrostat: steroid biosynthesis in human adrenocortical cells

Area of Science:

• Endocrinology
• Pharmacology
• Molecular Biology

Background:

• Aldosterone synthase (CYP11B2) is a key target for treating aldosterone-mediated hypertension.
• Selective inhibition of CYP11B2 is desired to minimize side effects associated with non-selective steroidogenesis inhibitors.

Purpose of the Study:

• To compare the functional selectivity of baxdrostat and osilodrostat in primary human adrenal cells.
• To evaluate their efficacy in suppressing aldosterone while preserving cortisol biosynthesis.

Main Methods:

• Ex vivo study using primary human adrenocortical cells from adenomas and normal tissue.
• Stimulation with ACTH and exposure to baxdrostat, osilodrostat, or metyrapone.
• Measurement of IC50 values, steroid profiling via LC-MS/MS, and molecular docking to CYP11B2 and CYP11B1.

Main Results:

• Baxdrostat selectively inhibited aldosterone (GM IC50 = 0.041 μM) with minimal cortisol suppression.
• Osilodrostat inhibited both aldosterone (GM IC50 = 0.0022 μM) and cortisol (GM IC50 = 0.196 μM).
• Baxdrostat showed modest 11-deoxycorticosterone increase (+3.76-fold), while osilodrostat caused larger increases (+25.4-fold) and androgen elevations. Molecular docking indicated stronger binding of baxdrostat to CYP11B2.

Conclusions:

• Baxdrostat exhibits greater functional selectivity for CYP11B2 compared to osilodrostat.
• Baxdrostat demonstrates a favorable profile with minimal impact on the cortisol axis and reduced precursor accumulation.
• These findings support baxdrostat's potential for selective aldosterone synthase inhibition in hypertension management.