CRF1 receptor

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.

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]

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].

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.

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.

[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.

C27H28CLFN2OS

483.04042

482.159

C, 67.14; H, 5.84; Cl, 7.34; F, 3.93; N, 5.80; O, 3.31; S, 6.64

752253-39-7

Crinecerfont hydrochloride;321839-75-2

5282340

Light yellow to yellow solid at room temperature

7.517

0

5

8

33

699

1

ClC1C=C(OC)C(C)=CC=1C1=C(C)SC(N(C(C2C=CC(C)=C(F)C=2)CC2CC2)CC#C)=N1

IEAKXXNRGSLYTQ-DEOSSOPVSA-N

InChI=1S/C27H28ClFN2OS/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/t24-/m0/s1

(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine

SSR125543; SSR-125543; SSR 125543; Crinecerfont; 752253-39-7; SSR 125,543; SSR-125,543; Crenessity; SSR125,543A; SSR-125543A; SSR 125543A; Crinecerfont

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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