Osilodrostat (LCI699) is a potent inhibitor of human 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) with IC50 values ​​of 2.5 and 0.7 nM, respectively, and has been approved by the FDA for the treatment of Cushing's disease.

Aldosterone synthase:0.7 nM, 11β-hydroxylase (human):IC50: 2.5 nM

METHODS: V79 or HEK-293 cell lines were treated with Osilodrostat (LCI699) (0-1000 nM). Aliquots of culture medium were removed after 5 hours, and steroids were extracted and analyzed by LC-MS/MS.
RESULTS In V79 cells expressing CYP11B1, osilodrostat (LCI699) inhibited the conversion of 11-deoxycortisol to cortisol with an IC5​​0 of 9.5 ± 0.5 nM. In contrast, in V79 cells expressing CYP11B2, LCI699 inhibited the conversion of corticosterone to aldosterone with an IC50 of 0.28 ± 0.06 nM. In V79 cells expressing CYP11A1, osilodrostat (LCI699) partially (<25%) inhibited pregnenolone formation at 1000 nM. In HEK-293 cells stably expressing CYP17A1 or CYP21A2, LCI699 showed negligible inhibition of activity (<1%) at concentrations up to 1000 nM. [5]

METHODS: Rats were randomly divided into single-sex groups and received daily doses of pasireotide (0.3 mg/kg/day, subcutaneous injection), Osilodrostat (LCI699) (20 mg/kg/day, oral), Osilodrostat (LCI699)/Pasireotide combination (low dose, 1.5/0.03 mg/kg/day; medium dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day) or vehicle for 13 weeks. Different doses of Osilodrostat (LCI699) and pasireotide alone and in combination were evaluated.
RESULTS Mean weight gain from baseline to week 13 was significantly lower in the pasireotide and combination treatment groups, whereas it was significantly higher in female rats treated with osilodrostat (LCI699) monotherapy; osilodrostat (LCI699) and pasireotide monotherapy were associated with significant changes in histology and mean weights of the pituitary and adrenal glands, liver, and ovaries/fallopian tubes; osilodrostat (LCI699) alone was associated with adrenal cortical hypertrophy and hepatocyte hypertrophy. [1]
METHODS: Osilodrostat (LCI699) was evaluated after oral administration (0.1-3 mg/kg for the Ang II model and 1-100 mg/kg for the ACTH model).
RESULTS Osilodrostat (LCI699) was rapidly absorbed (time to maximum plasma concentration [tmax] 0.3–2.4 hours) with a terminal elimination half-life (t½) of 2–5 hours. The pharmacokinetics of LCI699 were dose proportional over the dose range tested. Plasma protein binding was 35.9%.[4]

Sixty male and 60 female rats are randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, s.c.), osilodrostat (20 mg/kg/day, p.o.), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks.