{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:50:32Z","timestamp":1789645832721,"version":"4.0.0"},"reference-count":0,"publisher":"Bioscientifica","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/deed.en_GB"}],"content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Glucocorticoid stress hormones are produced in response to hypothalamic pituitary adrenal (HPA) axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR). Relacorilant is a highly selective GR antagonist currently undergoing a phase 3 clinical evaluation for the treatment of endogenous Cushing\u2019s syndrome. It was found that increases in serum ACTH and cortisol concentrations after relacorilant treatment were substantially less than the increases typically observed with mifepristone, but it is unclear what underlies these differences. In this study we set out to further preclinically characterize relacorilant in comparison to the classical but non-selective GR antagonist mifepristone. In human HEK-293 cells, relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling, and in human peripheral blood mononuclear cells relacorilant largely prevented the anti-inflammatory effects of dexamethasone. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by increased corticosterone exposure. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain. In mice, relacorilant induced a modest disinhibition of the HPA axis as compared to mifepristone. In line with this, in mouse pituitary cells, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release. This contrast between relacorilant and mifepristone is possibly due to the distinct transcriptional coregulator recruitment by the GR. In conclusion, relacorilant is thus an efficacious peripheral GR antagonist in mice with only modest disinhibition of the HPA axis, and the distinct properties of relacorilant endorse the potential of selective GR antagonist treatment for endogenous Cushing\u2019s syndrome.<\/jats:p>","DOI":"10.1530\/joe-22-0263","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T11:43:48Z","timestamp":1669635828000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":10,"title":["Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition"],"prefix":"10.1530","author":[{"given":"Eva MG","family":"Viho","sequence":"first","affiliation":[{"name":"E Viho, Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kroon","sequence":"additional","affiliation":[{"name":"J Kroon, Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Feelders","sequence":"additional","affiliation":[{"name":"R Feelders, Department of Internal Medicine, Division Endocrinology, Erasmus Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Houtman","sequence":"additional","affiliation":[{"name":"R Houtman, Research and Development, Precision Medicine Lab, Oss, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"van den Dungen","sequence":"additional","affiliation":[{"name":"E van den Dungen, Department of Internal Medicine, Division Endocrinology, Erasmus Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto M","family":"Pereira Arias","sequence":"additional","affiliation":[{"name":"A Pereira Arias, Department of Endocrinology and Metabolism, Amsterdam UMC Location AMC, Amsterdam, 1100AZ, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazel","family":"Hunt","sequence":"additional","affiliation":[{"name":"H Hunt, Research, Corcept Therapeutics, Menlo Park, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo J","family":"Hofland","sequence":"additional","affiliation":[{"name":"L Hofland, Department of Internal Medicine, Division Endocrinology, Erasmus Medical Center, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onno C","family":"Meijer","sequence":"additional","affiliation":[{"name":"O Meijer, Department of Medicine, Division Endocrinology, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/joe.bioscientifica.com\/view\/journals\/joe\/aop\/joe-22-0263\/joe-22-0263.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/joe.bioscientifica.com\/downloadpdf\/journals\/joe\/aop\/joe-22-0263\/joe-22-0263.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/joe.bioscientifica.com\/downloadpdf\/journals\/joe\/aop\/joe-22-0263\/joe-22-0263.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:57:48Z","timestamp":1784555868000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/joe\/article\/5556"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1530\/joe-22-0263","relation":{},"ISSN":["0022-0795","1479-6805"],"issn-type":[{"value":"0022-0795","type":"print"},{"value":"1479-6805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11]]}}}