Osilodrostat phosphate Chemical Properties

solubility 

H2O : ≥ 200 mg/mL (614.95 mM)

form 

Solid

color 

White to off-white

Osilodrostat phosphate Usage And Synthesis

FDA Approval

Osilodrostat received orphan drug designation from the USFDA and was approved in 2020 for the treatment of Cushing's disease.

Uses

Osilodrostat (LCI699) phosphate is a potent, orally active11β-hydroxylase (CYP11B1) inhibitor with an IC50 value of 35 nM. Osilodrostat phosphate is a potent, orally aldosterone synthase (CYP11B2) inhibitor with IC50 values of 0.7 nM and 160 nM for human aldosterone synthase and rat aldosterone synthase, respectively. Osilodrostat phosphate inhibits aldosterone and corticosterone synthesis. Osilodrostat phosphate has blood pressure lowering ability. Osilodrostat phosphate can be used for research of Cushing syndrome (CS)[1][2][3].

Mechanism of action

Osilodrostat Phosphate reduces cortisol production by inhibiting 11β-hydroxylase (CYP11B1), an enzyme that catalyzes the final step in the synthesis of adrenal cortex hormones.

Synthesis

Imidazole salt 158 was first protected with triphenylmethyl to generate triphenylmethylamine 159. Triphenylmethylamine 159 was reduced to give primary alcohol 160. Si-protection of primary alcohol 160 gave silyl ether 161 in 59% overall yield from this step. Imidazole 161 was alkylated with benzyl bromide 163 (prepared from arene 162 via Wohl-Ziegler conditions with N-bromosuccinimide (NBS) and dibenzoyl peroxide (DBPO) in 56% yield) in refluxing acrylonitrile. Removal of the triphenylmethyl protecting group using diethylamine gave benzylamine 164 in 75% overall yield from this step. Deprotonation of the benzyl proton of benzylamine 164 was followed by quenching with methyl chloroformate to give ester 165. Removal of the silyl ether protecting group by acid treatment was followed by conversion of the free alcohol to the mesylate. In the presence of NaI and a base, pyrrolimidazole 166 was obtained in 62% overall yield from this step. Saponification with aqueous base gave compound 167. The skeleton of oseltamivir was obtained as a racemate by thermal carboxylation. The (R)-enantiomer was separated by chiral high performance liquid chromatography (HPLC) with acetonitrile as the mobile phase. Finally, oseltamivir phosphate was obtained by phosphate formation.

in vivo

References

[1] Ménard J, et, al. Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects. J Transl Med. 2014 Dec 10;12:340. DOI:10.1186/s12967-014-0340-9
[2] Creemers SG, et, al. Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3437-3449. DOI:10.1210/jc.2019-00217
[3] Li L, et, al. Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats. Toxicol Appl Pharmacol. 2015 Aug 1;286(3):224-33. DOI:10.1016/j.taap.2015.05.004