Levoketoconazole

Levoketoconazole
	Skeletal structure of (2S,4R)-(−)-ketoconazole (levoketoconazole)
	3D representation of a levoketoconazole molecule
Clinical data
Trade names	Recorlev
Other names	COR-003; (2S,4R)-ketoconazole; NormoCort
License data	US DailyMed: Levoketoconazole;
Routes of; administration	By mouth
ATC code	H02CA04 (WHO) ;
Legal status
Legal status	US: ℞-only;
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	142128-57-2;
PubChem CID	47576;
DrugBank	DB05667;
ChemSpider	43284;
UNII	2DJ8R0NT7K;
KEGG	D10950;
ChEBI	CHEBI:47518;
ChEMBL	ChEMBL295698;
PDB ligand	KLN (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID60161949 ;
Chemical and physical data
Formula	C26H28Cl2N4O4
Molar mass	531.43 g·mol−1
3D model (JSmol)	Interactive image;
	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, sold under the brand name Recorlev, is a steroidogenesis inhibitor that is used for the treatment of Cushing's syndrome.²³⁴⁵ Levoketoconazole was approved for medical use in the United States in December 2021.⁶⁷

Levoketoconazole is the levorotatory or (2S,4R) enantiomer of ketoconazole,³⁴⁵ and it is an inhibitor of the enzymes CYP11B1 (11β-hydroxylase), CYP17A1 (17α-hydroxylase/17,20-lyase), and CYP21A2 (21-hydroxylase).²³⁵ It inhibits glucocorticoid biosynthesis and hence circulating levels of glucocorticoids, thereby treating Cushing's syndrome.²⁵ 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

"Recorlev- levoketoconazole tablet". DailyMed. 12 January 2022. Retrieved 20 February 2022.
"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.
"Levoketoconazole: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 3 January 2022. Retrieved 3 January 2022.
"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.
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.
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.

External links

Clinical trial number NCT03277690 for "A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome" at ClinicalTrials.gov
Clinical trial number NCT01838551 for "Treatment for Endogenous Cushing's Syndrome (SONICS)" at ClinicalTrials.gov

[Recorlev_FDA_label-1] "Recorlev- levoketoconazole tablet". DailyMed. 12 January 2022. Retrieved 20 February 2022.

[AdisInsight-2] "Levoketoconazole - Strongbridge Biopharma". AdisInsight. Springer Nature Switzerland AG.

[JrPace2016-3] 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.

[Geer2016-4] 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.

[Cuevas-RamosLim2016-5] 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.

[Thieroff-Ekerdt2016-8] 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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