osilodrostat   Click here for help

GtoPdb Ligand ID: 8310

Synonyms: Isturisa® | LCI-699 | LCI699
Approved drug PDB Ligand
osilodrostat is an approved drug (EMA & FDA (2020))
Compound class: Synthetic organic
Comment: Osilodrostat was designed as an inhibitor of aldosterone synthase (CYP11B2), but is also reported to inhibit the closely related enzyme, 11-beta-hydroxylase (CYP11B1) and hence as an inhibitor of cortisol biosynthesis [8]. It is this latter action of osilodrostat that is harnessed for clinical utility in Cushing's disease. The drug is orally bioavailable.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 2
Hydrogen bond donors 0
Rotatable bonds 1
Topological polar surface area 41.61
Molecular weight 227.09
XLogP 2.18
No. Lipinski's rules broken 0
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Canonical SMILES N#Cc1ccc(c(c1)F)C1CCc2n1cnc2
Isomeric SMILES N#Cc1ccc(c(c1)F)[C@H]1CCc2n1cnc2
InChI InChI=1S/C13H10FN3/c14-12-5-9(6-15)1-3-11(12)13-4-2-10-7-16-8-17(10)13/h1,3,5,7-8,13H,2,4H2/t13-/m1/s1
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Summary of Clinical Use Click here for help
Clinical efficacy of osilodrostat as a treatment for Cushing's disease (CD) was evaluated in Phase 3 clinical trial NCT02697734 [5]. The EMA granted osilodrostat orphan drug designation for the treatment of CD in late 2014 and granted full marketing authorisation for this indication in January 2020 [4]. The FDA's approval followed in March 2020.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
As a treatment for CD, osilodrostat's action as an inhibitor of CYP11B1, the enzyme responsible for the synthesis of cortisol from 11-deoxycortisol, is clinically effective [3,6]. Osilodrostat's inhibitory effect on CYP11B2 has been investigated as a therapy for controlling hypertension as inhibiting CYP11B2 reduces the synthesis of aldosterone [1-2,7], a key hormone in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and fluid balance.
Additional experimental CYP11B2 inhibitors with improved selectivity are described in [8].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02697734 Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease Phase 3 Interventional Novartis