Relacorilant

• Molecular FormulaC₂₇H₂₂F₄N₆O₃S
• Average mass586.561 Da

CAS 1496510-51-0

Phase III

UNII-2158753C7E

2158753C7E

[(4aR)-1-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone

[(4aR)-1-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone

Methanone, [(4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl][4-(trifluoromethyl)-2-pyridinyl]-

Methanone, ((4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4ah-pyrazolo(3,4-g)isoquinolin-4a-yl)(4-(trifluoromethyl)-2-pyridinyl)-

релакорилант[Russian][INN]

ريلاكوريلانت[Arabic][INN]

瑞拉可兰[Chinese][INN]

• OriginatorCorcept Therapeutics
• ClassAntineoplastics; Fluorine compounds; Isoquinolines; Ketones; Organic sulfur compounds; Pyrazoles; Pyridines; Small molecules
• Mechanism of ActionGlucocorticoid receptor antagonists
• Orphan Drug StatusYes – Pancreatic cancer; Cushing syndrome

• Phase IIICushing syndrome; Ovarian cancer; Pancreatic cancer
• Phase IIFallopian tube cancer; Peritoneal cancer; Prostate cancer
• Phase I/IISolid tumours
• Phase IAdrenocortical carcinoma

Most Recent Events

• 09 Sep 2022Subgroup analysis efficacy data from a phase-II trial in Ovarian cancer presented at the 47^th European Society for Medical Oncology Congress (ESMO-2022)
• 29 Jun 2022Phase-III clinical trials in Ovarian cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA (PO)
• 06 Jun 2022Corcept Therapeutics announces intentions to submit a NDA for Ovarian cancer

Relacorilant (developmental code name CORT-125134) is an antiglucocorticoid which is under development by Corcept Therapeutics for the treatment of Cushing’s syndrome.^[1] It is also under development for the treatment of solid tumors and alcoholism.^[1][2] The drug is a nonsteroidal compound and acts as an antagonist of the glucocorticoid receptor.^[1] As of December 2017, it is in phase II clinical trials for Cushing’s syndrome and phase I/II clinical studies for solid tumors, while the clinical phase for alcoholism is unknown.^[1]

Relacorilant is an orally available antagonist of the glucocorticoid receptor (GR), with potential antineoplastic activity. Upon administration, relacorilant competitively binds to and blocks GRs. This inhibits the activity of GRs, and prevents both the translocation of the ligand-GR complexes to the nucleus and gene expression of GR-associated genes. This decreases the negative effects that result from excess levels of endogenous glucocorticoids, like those seen when tumors overproduce glucocorticoids. In addition, by binding to GRs and preventing their activity, inhibition with CORT125134 also inhibits the proliferation of GR-overexpressing cancer cells. GRs are overexpressed in certain tumor cell types and promote tumor cell proliferation.

CLIP

https://europepmc.org/article/pmc/pmc8175224

Relacorilant (CORT125134)¹¹⁸⁾ is being developed by Corcept Therapeutics, Inc. It is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that may benefit from the modulation of cortisol activity. In structural optimization, the introduction of a trifluoromethyl group to the 4-position on the pyridyl moiety was found to increase HepG2 tyrosine amino transferase assay potency by a factor of four. Relacorilant is currently being evaluated in a phase II clinical study in patients with Cushing’s syndrome.¹¹⁹⁾

2-Bromo-4-(trifluoromethyl)pyridine (17) prepared from (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is employed as a key intermediate for the preparation of relacorilant as shown in Scheme 31.¹²⁰⁾

Scheme31. Synthesis of relacorilant.¹¹⁸⁾

118) H. Hunt, T. Johnson, N. Ray and I. Walters (Corcept Therapeutics, Inc.): PCT Int. Appl. WO2013/177559 (2013).

119) H. J. Hunt, J. K. Belanoff, I. Walters, B. Gourdet, J. Thomas, N. Barton, J. Unitt, T. Phillips, D. Swift and E. Eaton: Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J. Med. Chem. 60, 3405–3421 (2017). [Abstract] [Google Scholar]

120) B. Lehnemann, J. Jung and A. Meudt (Archimica GmbH): PCT Int. Appl. WO 2007/000249 (2007).

PAPER

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b00162

The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing’s syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing’s syndrome.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013177559

SYN

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Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide).

References

1. ^ Jump up to:^a b c d “Relacorilant – Corcept Therapeutics – AdisInsight”.
2. ^ Veneris JT, Darcy KM, Mhawech-Fauceglia P, Tian C, Lengyel E, Lastra RR, Pejovic T, Conzen SD, Fleming GF (2017). “High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer”. Gynecol. Oncol. 146 (1): 153–160. doi:10.1016/j.ygyno.2017.04.012. PMC 5955699. PMID 28456378.

External links

• Relacorilant – AdisInsight

Clinical data
Other names	CORT-125134
Routes of administration	By mouth
Drug class	Antiglucocorticoid
Identifiers
showIUPAC name
CAS Number	1496510-51-0
PubChem CID	73051463
ChemSpider	57617720
UNII	2158753C7E
KEGG	D11336
Chemical and physical data
Formula	C27H22F4N6O3S
Molar mass	586.57 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

//////////////Relacorilant, Phase III , Orphan Drug, Cushing syndrome, Ovarian cancer, Pancreatic cancer, релакорилант , ريلاكوريلانت , 瑞拉可兰 , 

CN1C=C(C=N1)S(=O)(=O)N2CCC3=CC4=C(CC3(C2)C(=O)C5=NC=CC(=C5)C(F)(F)F)C=NN4C6=CC=C(C=C6)F