CRF1 receptor
CRF1 receptor (corticotropin-releasing factor type 1 receptor). Crinecerfont is a highly potent and selective CRF1 receptor antagonist. It binds to the CRF1 receptor with a Ki value of 2 nM and blocks CRF binding to pituitary CRF1 receptors. This inhibition reduces CRF1 receptor-mediated ACTH secretion from the anterior pituitary. In CAH, reduction of ACTH decreases adrenal androgen production and lowers levels of steroid precursors such as 17-hydroxyprogesterone (17OHP). CRF1 receptor antagonism also regulates stress responses, fear, and anxiety behaviors through central effects in the brain.

Crinecerfont exerts its therapeutics effects via selective antagonism of corticotropin releasing factor (CRF) type 1 receptor, which is abundant in the pituitary gland. It blocks the binding of CRF to CRF type 1 receptors in the pituitary gland, which inhibits the secretion of adrenocorticotropic hormone (ACTH) from the pituitary. This reduction in ACTH leads to decreased adrenal androgen production and lower levels of steroid precursors, such as 17OH-progesterone.

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In cell-free biochemical assays, crinecerfont binds to the human CRF1 receptor with high affinity. The Ki (inhibition constant) is 2 nM, determined using competition binding assays with radiolabeled CRF or CRF-like ligands. The compound shows no significant binding to CRF2 receptors or other GPCRs at concentrations up to 10 uM, indicating high selectivity for CRF1. The antagonist potency is confirmed by measuring inhibition of CRF-stimulated cAMP accumulation in cell lines expressing recombinant CRF1 receptors. Crinecerfont acts as a competitive antagonist at the orthosteric binding site.

In eight adult patients with CAH administered the recommended dosage of crinecerfont for two weeks, the median percent reduction from baseline in ACTH was 62%. In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended crinecerfont dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels of 65% in one study and 72% in the other. Patients undergoing treatment with crinecerfont must continue concomitant glucocorticoid replacement therapy. Doses should be maintained at (or above) the dose required for cortisol replacement. Any dose adjustments should be performed under the supervision of a health care provider.

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The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure.[2]

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Crinecerfont exerts its therapeutic effects via selective antagonism of CRF1 receptors. It blocks CRF binding to CRF1 receptors, inhibiting CRF1 receptor-mediated signaling. In vitro, crinecerfont inhibits CRF-stimulated cAMP production in cells expressing recombinant human CRF1 receptors. The IC50 for inhibition of CRF-induced cAMP accumulation is in the low nanomolar range, consistent with its high binding affinity. In the pituitary, blockade of CRF1 receptors leads to reduced ACTH secretion. In clinical studies, crinecerfont treatment significantly reduces ACTH levels in patients. The compound also attenuates stress-induced behavioral responses in animal models of anxiety and PTSD.

CRF1 receptor binding is evaluated using competition binding assays with radiolabeled ligands. Cell membranes prepared from HEK293 or CHO cells expressing recombinant human CRF1 receptors are used. Membranes are incubated with 0.02-0.1 nM [¹2⁵I]-Tyr⁰-CRF or [3H]-CRF in the presence of increasing concentrations of crinecerfont (0.01-1000 nM) for 1-2 hours at room temperature. Bound radioactivity is separated by filtration through glass fiber filters, and the filters are washed and counted. Nonspecific binding is determined in the presence of 1 uM unlabeled CRF or a saturating concentration of a CRF1 antagonist. Ki values are calculated from IC50 values using the Cheng-Prusoff equation.

For cAMP inhibition assays, cells expressing CRF1 receptors are seeded in 96-well plates, pre-incubated with crinecerfont (0.01-1000 nM) for 15-30 minutes, then stimulated with CRF (EC80, usually 0.1-10 nM) for 30 minutes. cAMP levels are measured using HTRF or AlphaScreen-based cAMP detection kits. IC50 values are calculated.

SSR125543 was suspended in saline with methylcellulose (0.6%) and Tween 80 (0.1%) to obtain concentrations of 1.0 mg/ml. The treatments began five hours after stress. Mice received one intraperitoneal (i.p.) administration per day of 10 ml/kg. The last administration was performed 30 min before the start of EEG recordings. The doses were validated in a previous study using the same procedure and the same species. It showed that 10 mg/kg represented the optimal dose to seek efficacy in this model [2].

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Crinecerfont has been evaluated in multiple in vivo models. In eight adult patients with classic CAH administered the recommended dosage for two weeks, the median percent reduction from baseline in ACTH was 62%. In Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended crinecerfont dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels of 65% in one study and 72% in the other. In preclinical models, crinecerfont (SSR125543) at 10 mg/kg/day i.p. for 2 weeks attenuates sleep/wakefulness impairment induced by traumatic stress exposure in a mouse model of PTSD. The compound also shows efficacy in models of anxiety and depression. Clinical dosing: 50-200 mg oral once or twice daily.

Absorption
In adult patients, the AUC0-24h and Cmax of clinsulfanilamide at steady state were 72,846 ngh/mL and 4,231 ng/mL, respectively. In pediatric patients, the AUC0-24h ranged from 47,062 to 74,693 ngh/mL, and the Cmax ranged from 2,887 to 4,555 ng/mL, depending on the dose. The median time to reach Cmax (Tmax) was 4 hours.
Elimination Route
Following a single oral dose of 100 mg of radiolabeled clinsulfanilamide, approximately 47.3% of the dose was recovered in feces (2.7% of which was the original drug) and 2% was recovered in urine (the original drug was not detected).
Volume of Distribution
The mean apparent volume of distribution of clinsulfanilamide in adults is 852 liters.
Clearance
The apparent clearance of clindamycin is 3.5 L/h.
Protein Binding
Clindamycin has a high protein binding rate in plasma (≥99.9%).
Metabolism/Metabolites
In vitro studies have shown that clindamycin is primarily metabolized by CYP3A4, with a smaller metabolic role by CYP2B6. Additionally, CYP2C8 and CYP2C19 may also contribute slightly to the metabolism of clindamycin.
Biological Half-Life
The effective half-life of clindamycin is approximately 14 hours.

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PK parameters for crinecerfont have been characterized in clinical studies. The compound is rapidly absorbed following oral administration, with Tmax typically achieved in 1-3 hours. Terminal half-life (t1/2) is approximately 6-12 hours, supporting once- or twice-daily dosing. The compound has dose-proportional PK over the clinical dose range (50-200 mg). Plasma protein binding is moderate-to-high. The compound is metabolized primarily by CYP3A4 in the liver. Excretion is via both renal and fecal routes. The absolute oral bioavailability has not been fully disclosed but is expected to be moderate to high. In patients with CAH, the reduction in ACTH and adrenal androgen levels correlates with plasma drug concentrations. Therapeutic drug monitoring is not routinely required.

Hepatotoxicity
In registration clinical trials, the incidence of liver dysfunction during clindamycin treatment was low and not significantly different from the placebo group. No cases of ALT or AST elevations exceeding 3 times the upper limit of normal (ULN) were observed, nor were there any cases of liver injury accompanied by jaundice or other symptoms. Clinical experience with clindamycin is limited, but there are currently no published reports of clinically significant liver injury. Probability score: E (unlikely to cause clinically significant liver injury).
Use during pregnancy and lactation
◉Overview of use during lactation
There is currently no information regarding the use of clindamycin during lactation. Because clindamycin binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk is likely to be low. If the mother requires clindamycin, breastfeeding does not need to be discontinued. Adrenal insufficiency symptoms, such as weakness, reduced feeding intake, and weight loss, should be monitored in breastfed infants.
◉Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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In Phase 3 clinical trials of adults and pediatric patients with classic congenital adrenal hyperplasia (CAH), crinecerfont was generally well-tolerated. The most common adverse events (≥5%) include fatigue, headache, nausea, diarrhea, abdominal pain, and upper respiratory tract infection. Most adverse events are mild to moderate in severity. Crinecerfont does not cause significant changes in laboratory parameters, including liver function tests or serum electrolytes. No serious treatment-related adverse events have been reported at therapeutic doses. Long-term safety studies are ongoing. Preclinical toxicology studies in animals showed no target organ toxicity at exposures substantially higher than therapeutic exposures. The compound is not genotoxic or carcinogenic in standard assays. Crinecerfont is not associated with QT prolongation or other cardiac safety signals.

[1]. https://pubchem.ncbi.nlm.nih.gov/compound/5282340
[2]. The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine. Behav Brain Res. 2015 Feb 15;279:41-6.

SSR 125543 is an amine drug.

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Drug Indications
Treatment of atypical hemolytic uremic syndrome, treatment of paroxysmal nocturnal hemoglobinuria
Treatment of congenital adrenocortical hyperplasia
Drug Indications
Crinecerfont is indicated for adults and children aged 4 years and older with classic congenital adrenocortical hyperplasia (CAH) as adjunctive therapy to control androgen levels.
Treatment of atypical hemolytic uremic syndrome, treatment of paroxysmal nocturnal hemoglobinuria
Hepatotoxicity Overview
Crinecerfont is a small molecule corticotropin-releasing factor receptor inhibitor used to treat patients with congenital adrenocortical hyperplasia. No significant increase in serum transaminase levels or clinically significant liver injury was observed during treatment with Crinecerfont. Patients with congenital adrenal hyperplasia (CAH) face two main problems: adrenal insufficiency due to insufficient endogenous cortisol secretion and androgen excess due to excessive pituitary secretion of adrenocorticotropic hormone (ACTH). Standard treatment includes cortisol replacement therapy, but often requires supraphysiological doses of glucocorticoids to lower ACTH and adrenal androgen levels, leading to chronic glucocorticoid overexposure. The majority of poor outcomes in CAH patients stem from the inability to precisely adjust glucocorticoid dosage, failing to adequately replace cortisol deficiency or adequately suppress androgen overexposure. Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist that reduces excessive ACTH secretion from the pituitary gland. In patients with CAH, when used in combination with glucocorticoid replacement therapy, Crinecerfont can reduce the dosage of glucocorticoid replacement therapy, thereby reducing the risk of glucocorticoid overexposure. Crinecerfont was approved by the FDA in December 2024 as adjunctive therapy for patients with congenital adrenocortical hyperplasia (CAH). Crinecerfont is a type 1 corticotropin-releasing factor receptor antagonist. Its mechanism of action is as a type 1 corticotropin-releasing factor receptor antagonist. Crinecerfont is a small molecule inhibitor of the corticotropin-releasing factor receptor used to treat patients with congenital adrenocortical hyperplasia. No significant elevations in serum transaminase levels or clinically significant liver injury were observed during Crinecerfont treatment. Crinecerfont is a small molecule drug currently in Phase IV clinical trials (covering all indications), first approved in 2024 for the treatment of congenital adrenocortical hyperplasia, and has one investigational indication.

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Crinecerfont (SSR-125543) hydrochloride is being developed by Neurocrine Biosciences for the treatment of classic congenital adrenal hyperplasia (CAH). As of 2024, crinecerfont has completed Phase 3 clinical trials in both adults and pediatric patients with CAH. In Phase 2 studies, crinecerfont treatment for 4 weeks significantly reduced ACTH levels and adrenal androgen precursors (17OHP) in patients. The compound has also been investigated in clinical trials for post-traumatic stress disorder (PTSD), major depressive disorder, and generalized anxiety disorder. Crinecerfont is also known as SSR-125543A, SSR125543, and NBI-74788. The compound contains an alkyne group and can be used for click chemistry applications (copper-catalyzed azide-alkyne cycloaddition, CuAAc). The hydrochloride salt form improves water solubility for oral and injection administration. As of 2026, crinecerfont is not yet approved by the FDA or EMA, but regulatory submissions are under review. The molecular formula is C27H26ClFN2OS·HCl or similar (exact formula may vary by salt form), with molecular weight approximately 519.5. The compound is intended for research use only in a laboratory setting and is not for human consumption outside of approved clinical trials.

C27H28N2OFSCL.HCL

519.50136

518.136

321839-75-2

Crinecerfont;752253-39-7

9806689

Light yellow to yellow solid powder

1

5

8

34

699

1

CC1=C(C=C(C=C1)[C@H](CC2CC2)N(CC#C)C3=NC(=C(S3)C)C4=C(C=C(C(=C4)C)OC)Cl)F.Cl

BMXALUHUEGRRCH-JIDHJSLPSA-N

InChI=1S/C27H28ClFN2OS.ClH/c1-6-11-31(24(13-19-8-9-19)20-10-7-16(2)23(29)14-20)27-30-26(18(4)33-27)21-12-17(3)25(32-5)15-22(21)28;/h1,7,10,12,14-15,19,24H,8-9,11,13H2,2-5H3;1H/t24-;/m0./s1

4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine;hydrochloride

321839-75-2; SSR 125543A; Crinecerfont (hydrochloride); SSR 125543 hydrochloride; 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine;hydrochloride;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~192.49 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)