Levoketoconazole

Levoketoconazole, sold under the brand name Recorlev, is a steroidogenesis inhibitor that is used for the treatment of Cushing's syndrome.[2][3][4][5] Levoketoconazole was approved for medical use in the United States in December 2021.[6][7]

Levoketoconazole
Clinical data
Trade namesRecorlev
Other namesCOR-003; (2S,4R)-ketoconazole; NormoCort
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
IUPAC name
  • 1-[4-(4-{[(2S,4R)-2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-1-piperazinyl]ethanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H28Cl2N4O4
Molar mass531.43 g·mol−1
3D model (JSmol)
SMILES
  • CC(=O)N1CCN(CC1)c2ccc(cc2)OC[C@@H]3CO[C@@](O3)(Cn4ccnc4)c5ccc(cc5Cl)Cl
InChI
  • InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m1/s1
  • Key:XMAYWYJOQHXEEK-ZEQKJWHPSA-N

Levoketoconazole is the levorotatory or (2S,4R) enantiomer of ketoconazole,[3][4][5] and it is an inhibitor of the enzymes CYP11B1 (11β-hydroxylase), CYP17A1 (17α-hydroxylase/17,20-lyase), and CYP21A2 (21-hydroxylase).[2][3][5] It inhibits glucocorticoid biosynthesis and hence circulating levels of glucocorticoids, thereby treating Cushing's syndrome.[2][5] 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.[5] 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.[8]

References
  1. "Recorlev- levoketoconazole tablet". DailyMed. 12 January 2022. Retrieved 20 February 2022.
  2. "Levoketoconazole - Strongbridge Biopharma". AdisInsight. Springer Nature Switzerland AG.
  3. 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.
  4. 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.
  5. 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.
  6. "Levoketoconazole: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 3 January 2022.
  7. "Xeris Biopharma Announces U.S. FDA Approval of Recorlev (levoketoconazole) for the Treatment of Endogenous Hypercortisolemia in Adult Patients With Cushing's Syndrome" (Press release). Xeris Biopharma. 30 December 2021. Retrieved 3 January 2022 – via Business Wire.
  8. 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.
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