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| Targets |
CORT-108297 targets the glucocorticoid receptor (GR), a nuclear receptor that mediates the effects of glucocorticoid hormones such as cortisol. It is a high-affinity, specific GR antagonist with a Ki of 0.45 nM. The compound shows binding affinity for human glucocorticoid receptor of 0.6 nM and glucocorticoid receptor functional antagonism of 6.8 nM as measured in a reporter gene assay. It has no affinity for other steroid receptors, confirming its selectivity. By blocking GR, CORT-108297 inhibits glucocorticoid-mediated gene transcription.
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| ln Vitro |
When compared to treatment with R1881/Enzalutamide (RE) alone, combination therapy with dexamethasone increased steady-state SGK1 expression in LAPC4 cells by a factor of 1.7. The dexamethasone-induced SGK1 expression was 50% suppressed by the addition of CORT118335 (1μM), whereas the dexamethasone-mediated rise in SGK1 was totally prevented by Cort108297 (p<0.05). When compared to RE therapy, dexamethasone enhanced KLK3 expression 2.5 times. Both CORT118335 and Cort108297 inhibited KLK3 expression produced by dexamethasone (48% and 60% inhibition, respectively, p<0.05). In CWR-22Rv1 cells, dexamethasone ± SGRM for three days resulted in a significant 100-fold increase in SGK1 gene expression as compared to RE-treated cells. Cort108297 and CORT118335 fully eliminated this induction (p<0.01). In CWR-22Rv1 cells, dexamethasone also increased KLK3 (7.5-fold) in comparison to RE; this induction was reduced by 70% and 75%, respectively, by Cort108297 and CORT118335 (p<0.01) [2].
In vitro, CORT-108297 is a high-affinity GR antagonist with a Ki of 0.45 nM. It has binding affinity for human GR of 0.6 nM and functional antagonism of 6.8 nM in reporter gene assays. In cell-based studies, CORT-108297 has been shown to suppress dexamethasone-induced gene expression. In LAPC4 cells, CORT-108297 completely prevented the dexamethasone-mediated rise in SGK1 expression (p<0.05) and inhibited KLK3 expression by 60% (p<0.05). In CWR-22Rv1 cells, CORT-108297 fully eliminated dexamethasone-induced SGK1 gene expression (p<0.01) and reduced KLK3 expression by 70% (p<0.01). |
| ln Vivo |
Male C57BL/6J mice aged ten weeks were given a meal consisting of 60% fat calories and water enhanced with 11% sucrose for a duration of four weeks. Cort108297 (80 mg/kg QD), Cort108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or carrier were administered to the group (n = 8). Compared to mice given a high-fat, high-sugar diet alone, mice given a high-fat, high-sugar diet plus mifepristone or Cort108297 lost a substantial amount of weight. Mice receiving either Cort108297 40 mg/kg BID or Cort108297 80 mg/kg QD had significantly lower levels of stable plasma glucose at the conclusion of the 4-week treatment period compared to those receiving vehicle [3]. Male rats were subjected to a forced swim test (FST) or restraint stress after receiving treatment with mifepristone (10 mg/kg), Cort108297 (30 mg/kg and 60 mg/kg), imipramine (10 mg/kg), or vehicle for five days. Cort108297 successfully suppressed the peak corticosterone response to restraint stress and FST at both dosages. In the forced swim test (FST), immobility was only considerably decreased by the higher dosage of Cort108297 (60 mg/kg) [4].
In vivo, CORT-108297 has been studied in mouse models of metabolic and stress-related disorders. In male C57BL/6J mice fed a high-fat, high-sugar diet, CORT-108297 (80 mg/kg QD or 40 mg/kg BID) caused substantial weight loss compared to vehicle. Mice receiving CORT-108297 had significantly lower levels of stable plasma glucose at the end of the 4-week treatment period. In a forced swim test and restraint stress model, CORT-108297 (30 mg/kg and 60 mg/kg) successfully suppressed the peak corticosterone response to stress, and the higher dose (60 mg/kg) significantly decreased immobility in the forced swim test. |
| Enzyme Assay |
In vitro receptor binding assays for CORT-108297 measure its affinity for the glucocorticoid receptor. Membranes from cells expressing the GR are incubated with a radiolabeled GR ligand (e.g., [3H]dexamethasone) and varying concentrations of CORT-108297. The Ki is determined from competition binding curves. Functional assays measure the compound's ability to antagonize GR-mediated transcription. Cells are transfected with a glucocorticoid response element (GRE)-luciferase reporter and treated with a GR agonist (e.g., dexamethasone) in the presence of CORT-108297. The inhibition of luciferase activity is measured, and the IC50 for functional antagonism is determined.
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| Cell Assay |
In vitro cell-based assays for CORT-108297 are used to study its effects on GR-mediated gene expression. Cells (e.g., LAPC4 or CWR-22Rv1 prostate cancer cells) are treated with dexamethasone in the presence or absence of CORT-108297. The expression of GR target genes such as SGK1 and KLK3 is measured by quantitative PCR or Western blotting. CORT-108297 has been shown to suppress dexamethasone-induced SGK1 and KLK3 expression in a dose-dependent manner. These assays confirm the compound's potent GR antagonistic activity in a cellular context.
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| Animal Protocol |
In vivo animal experiments for CORT-108297 are conducted in mouse models of metabolic and stress-related disorders. In a high-fat, high-sugar diet model, male C57BL/6J mice are treated with CORT-108297 (80 mg/kg QD or 40 mg/kg BID) for 4 weeks, and body weight, plasma glucose, and other metabolic parameters are measured. In stress response studies, rats are treated with CORT-108297 (30 mg/kg or 60 mg/kg) for 5 days, subjected to forced swim test or restraint stress, and corticosterone levels and immobility are measured. These studies confirm the in vivo efficacy of CORT-108297 in modulating GR signaling.
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| ADME/Pharmacokinetics |
CORT-108297 has a molecular formula that is not specified in standard product descriptions. It is a solid compound with a purity of ≥98%. It is soluble in DMSO and other organic solvents. For storage, it is recommended to keep the powder at -20°C. Detailed pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) have been characterized in preclinical studies. In animal studies, CORT-108297 has been administered orally.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for CORT-108297 is not provided in standard product descriptions. As a research compound, its toxicity profile has not been extensively characterized. In vivo studies have used doses up to 80 mg/kg in mice without reported overt toxicity. However, as a GR antagonist, it may affect glucocorticoid-mediated physiological processes, and long-term use could have potential side effects. As with all research chemicals, standard laboratory safety precautions should be followed when handling CORT-108297. Its use is limited to research applications and it is not intended for human or veterinary use.
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| References |
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| Additional Infomation |
CORT-108297 is a research compound and is not approved for any clinical or therapeutic use. It is a high-affinity, specific glucocorticoid receptor (GR) antagonist with a Ki of 0.45 nM. It is a selective glucocorticoid receptor modulator with no affinity for other steroid receptors. CORT-108297 has been shown to suppress glucocorticoid-induced gene expression and to have effects on body weight, glucose metabolism, and stress responses in animal models. It is a valuable research tool for studying glucocorticoid receptor signaling and potential therapeutic applications in metabolic and psychiatric disorders.
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| Exact Mass |
535.155
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| CAS # |
1018679-79-2
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| PubChem CID |
44454750
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| Appearance |
White to off-white solid powder
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| LogP |
6.105
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
940
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=S(N1C[C@@]2(COCC)CC3=C(N(C4=CC=C(F)C=C4)N=C3)C=C2CC1)(C5=CC=C(C(F)(F)F)C=C5)=O
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| InChi Key |
SLKURXRZHJOZOD-RUZDIDTESA-N
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| InChi Code |
InChI=1S/C26H25F4N3O3S/c1-2-36-17-25-14-18-15-31-33(22-7-5-21(27)6-8-22)24(18)13-20(25)11-12-32(16-25)37(34,35)23-9-3-19(4-10-23)26(28,29)30/h3-10,13,15H,2,11-12,14,16-17H2,1H3/t25-/m1/s1
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| Chemical Name |
(4aR)-4a-(ethoxymethyl)-1-(4-fluorophenyl)-6-[4-(trifluoromethyl)phenyl]sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinoline
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| Synonyms |
CORT-108297 CORT108297 CORT 108297
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04601038 | RECRUITING | Drug: CORT108297 Drug: Placebo |
Alzheimer Disease Memory Impairment Mild Cognitive Impairment |
Johns Hopkins University | 2021-06-28 | Phase 2 |
| NCT04452500 | RECRUITING | Drug: CORT108297 Drug: Placebo |
PTSD | VA Office of Research and Development | 2022-10-15 | Phase 2 |
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