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

Hunt, Hazel; Belanoff, Joseph K.; Walters, Iain A. S.; Gourdet, Benoit; Thomas, Jennifer A.; Barton, Naomi; Unitt, John; Phillips, Timothy D.; Swift, Denise; Eaton, Emily P.

doi:10.1021/acs.jmedchem.7b00162

Cited by 55 publications

(47 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CORT125134 represents such a compound and is being developed for the treatment of patients with Cushing syndrome. Efficacy equivalent to mifepristone has been demonstrated in a rat model of exogenous Cushing syndrome and a phase 2 clinical study in this indication is under way.…”

Section: Discussionmentioning

confidence: 99%

“…CORT125134 [( R )‐(1‐(4‐fluorophenyl)‐6‐((1‐methyl‐1 H ‐pyrazol‐4‐yl)sulfonyl)‐4,4a,5,6,7,8‐hexahydro‐1 H ‐pyrazolo[3,4‐g]isoquinolin‐4a‐yl)(4‐(trifluoromethyl)pyridin‐2‐yl)methanone] is a small molecule being developed for indications that may benefit from the modulation of cortisol activity (Figure ). CORT125134 is an orally active, high‐affinity antagonist of the glucocorticoid receptor (GR) with excellent selectivity for the GR over other steroid receptors . The clinical relevance of GR modulation has been demonstrated in a number of settings, most notably Cushing syndrome.…”

mentioning

confidence: 99%

“…CORT125134 is an orally active, high-affinity antagonist of the glucocorticoid receptor (GR) with excellent selectivity for the GR over other steroid receptors. 1 The clinical relevance of GR modulation has been demonstrated in a number of settings, most notably Cushing syndrome. Mifepristone (Korlym R ) is marketed in the United States for the control of hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing syndrome.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Hunt

Donaldson

Strem

et al. 2017

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

CORT125134 is an orally active, high‐affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first‐in‐human study was conducted to evaluate the dose‐related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty‐one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high‐fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half‐life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Hunt

Donaldson

Strem

et al. 2017

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

show abstract

“…Table 3 includes the limited number of SEGRAMs that are in clinical trials for cancer treatment, one of which is relacorilant (CORT125134). Phase I and II clinical trials are currently underway with relacorilant in combination with nab-paclitaxel for the solid tumors [232]. Another highly potent GR antagonist ORIC-101, which is used for CRPC in AR+ tumors, has shown antitumor effects by promoting a response to chemotherapy in an ovarian cancer xenograft model [233].…”

Section: Glucocorticoid Receptor (Gr) Inhibitorsmentioning

confidence: 99%

Transcription Factors in Cancer Development and Therapy

Vishnoi

Viswakarma

Rana

et al. 2020

Cancers

103

View full text Add to dashboard Cite

Cancer is a multi-step process and requires constitutive expression/activation of transcription factors (TFs) for growth and survival. Many of the TFs reported so far are critical for carcinogenesis. These include pro-inflammatory TFs, hypoxia-inducible factors (HIFs), cell proliferation and epithelial–mesenchymal transition (EMT)-controlling TFs, pluripotency TFs upregulated in cancer stem-like cells, and the nuclear receptors (NRs). Some of those, including HIFs, Myc, ETS-1, and β-catenin, are multifunctional and may regulate multiple other TFs involved in various pro-oncogenic events, including proliferation, survival, metabolism, invasion, and metastasis. High expression of some TFs is also correlated with poor prognosis and chemoresistance, constituting a significant challenge in cancer treatment. Considering the pivotal role of TFs in cancer, there is an urgent need to develop strategies targeting them. Targeting TFs, in combination with other chemotherapeutics, could emerge as a better strategy to target cancer. So far, targeting NRs have shown promising results in improving survival. In this review, we provide a comprehensive overview of the TFs that play a central role in cancer progression, which could be potential therapeutic candidates for developing specific inhibitors. Here, we also discuss the efforts made to target some of those TFs, including NRs.

show abstract

“…CORT125281 is a novel GR antagonist that is being developed to counteract pathologies that result from overactive GC signaling (Hunt et al 2017). Unlike mifepristone, CORT125281 lacks cross-reactivity with other nuclear receptors (Kroon et al 2018).…”

Section: Introductionmentioning

confidence: 99%

The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity

Koorneef

Kroon

Viho

et al. 2020

Journal of Endocrinology

View full text Add to dashboard Cite

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

show abstract

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

Cited by 55 publications

References 18 publications

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Transcription Factors in Cancer Development and Therapy

The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity

Contact Info

Product

Resources

About