Levoketoconazole
Levoketoconazole (INN, USAN) (developmental code name COR-003; tentative brand name Recorlev, previously NormoCort), also known as (2S,4R)-ketoconazole, is a steroidogenesis inhibitor that is under development by Strongbridge Biopharma (formerly Cortendo AB) for the treatment of Cushing's syndrome.[1][2][3][4] It is currently in phase III clinical trials for this indication.[1][2] The drug is the levorotatory or (2S,4R) enantiomer of ketoconazole.[2][3][4] It is expected to have greater potency, efficacy, and safety, including a lower risk of hepatotoxicity, relative to racemic ketoconazole.[3][4]
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| Trade names | Recorlev |
| Other names | COR-003; (2S,4R)-ketoconazole; NormoCort |
| Routes of administration | By mouth |
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| Formula | C26H28Cl2N4O4 |
| Molar mass | 531.43 g·mol−1 |
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Levoketoconazole is an inhibitor of the enzymes CYP11B1 (11β-hydroxylase), CYP17A1 (17α-hydroxylase/17,20-lyase), and CYP21A2 (21-hydroxylase).[1][2][4] It inhibits glucocorticoid biosynthesis and hence circulating levels of glucocorticoids, thereby treating Cushing's syndrome.[1][4] In addition to its increased potency, the drug is 12-fold less potent than racemic ketoconazole in inhibiting CYP7A1 (cholesterol 7α-hydroxylase), theoretically resulting in further reduced interference with bile acid production and metabolite elimination and therefore less risk of hepatotoxicity.[4] Levoketoconazole has also been found to inhibit CYP11A1 (cholesterol side-chain cleavage enzyme) and CYP51A1 (lanosterol-14α-demethylase), similarly but more potently relative to ketoconazole.[5]
References
- "Levoketoconazole - Strongbridge Biopharma". AdisInsight. Springer Nature Switzerland AG.
- Laws Jr ER, Pace L (11 November 2016). Cushing's Disease: An Often Misdiagnosed and Not So Rare Disorder. Elsevier Science. pp. 113–. ISBN 978-0-12-804390-5.
- Geer EB (1 December 2016). The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease: Cushing's Syndrome and Beyond. Springer. pp. 170–. ISBN 978-3-319-45950-9.
- Cuevas-Ramos D, Lim DS, Fleseriu M (2016). "Update on medical treatment for Cushing's disease". Clinical Diabetes and Endocrinology. 2 (1): 16. doi:10.1186/s40842-016-0033-9. PMC 5471955. PMID 28702250.
- Thieroff-Ekerdt R, Lavin P, Abou-Gharbia M, France N (October 2016). Pharmacology of COR-003 (levoketoconazole), an investigational treatment for endogenous Cushing's syndrome (PDF). Pituitary disorders—it’s not the anterior pituitary (posters). Endocrine Society. pp. SAT-547–SAT-547. doi:10.1210/endo-meetings.2016.np.15.sat-547.