SUN-245 In Vitro Study of the Effects of the Novel Aldosterone Synthase Inhibitor Baxdrostat

Abstract Disclosure: Y. Taki: None. T. Kono: None. I. Sakuma: None. T. Tanaka: None. Objective: The novel aldosterone synthase inhibitor Baxdrostat (Bax) has demonstrated significant antihypertensive effects in patients with refractory hypertension, with ongoing clinical trials. This study investigates the effects of Bax on the steroidogenic system using patient-derived adrenal tumor cells. Methods: Primary cultures were established using adrenal tumor tissue obtained from patients with aldosterone-producing adenoma (APA) (n = 10) and cortisol-producing tumors (CPT) (n = 10). Bax, Osilodrostat (Osi), and Metyrapone (Met) were added to the culture medium at concentrations ranging from 0.0001 to 10 μM. After three days, aldosterone (Ald) (measured via CLEIA) and cortisol (F) (measured via ECLIA) concentrations in the culture medium were quantified, and the respective IC50 values were compared. Additionally, steroid intermediate metabolites were analyzed in selected cases using LC-MS/MS. Docking simulations (DS) of the drugs with steroid synthases were performed using AutoDock Vina. Results: In APA cells, the IC50 of Bax for Ald was 0.063 μM, with Osi (0.003 μM) and Met (1.310 μM) showing dose-dependent inhibitory effects. In CPT cells, Bax exhibited a weaker inhibitory effect on F compared to Osi (IC50: 0.438 μM) and Met (0.748 μM). Bax induced a concentration-dependent increase in 11-deoxycorticosterone (DOC) in APA cells, though the increase was lower than that observed with Osi. Similarly, in CPT cells, Bax resulted in a smaller accumulation of corticosterone, 11-DOC, and 11-deoxycortisol compared to Osi. DS analysis revealed that the tetrahydroisoquinoline structure of Bax binds to the heme iron of CYP11B2, with an estimated binding affinity of -11.5 kcal/mol. Discussion: Bax demonstrated inhibitory effects on CYP11B2, supporting its potential as a therapeutic option for primary aldosteronism. Its weaker inhibitory effect on CYP11B1 in CPT cells, compared to Osi, suggests a reduced risk of side effects, making it a promising candidate for clinical application. Presentation: Sunday, July 13, 2025