Levoketoconazole

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Levoketoconazole
Levoketoconazole.svg
Clinical data
Trade names Recorlev
Other namesCOR-003; (2S,4R)-ketoconazole; NormoCort
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 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
Formula C26H28Cl2N4O4
Molar mass 531.43 g·mol−1
3D model (JSmol)
  • CC(=O)N1CCN(CC1)c2ccc(cc2)OC[C@@H]3CO[C@@](O3)(Cn4ccnc4)c5ccc(cc5Cl)Cl
  • 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, 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]

Contents

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]

Research

In a systematic review of levoketoconazole, published in 2024, it was found to be effective in the management of Cushing Syndrome. [9]

References

  1. ↑ "Recorlev- levoketoconazole tablet". DailyMed. 12 January 2022. Retrieved 20 February 2022.
  2. 1 2 3 "Levoketoconazole - Strongbridge Biopharma". AdisInsight. Springer Nature Switzerland AG.
  3. 1 2 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. 1 2 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. 1 2 3 4 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). Archived from the original on 3 January 2022. 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. Archived from the original (PDF) on 20 September 2020. Retrieved 30 April 2017.
  9. ↑ Patra S, Dutta D, Nagendra L, Raizada N (2024). "Efficacy and Safety of Levoketoconazole in Managing Cushing's Syndrome: A Systematic Review". Indian Journal of Endocrinology and Metabolism. 28 (4): 343–349. doi: 10.4103/ijem.ijem_477_23 . PMC   11451957 . PMID   39371660.
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