 HCl Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C27H28N2OFSCL.HCL |
| Molecular Weight | 519.50136 |
| Exact Mass | 518.136 |
| CAS # | 321839-75-2 |
| Related CAS # | Crinecerfont;752253-39-7 |
| PubChem CID | 9806689 |
| Appearance | Light yellow to yellow solid powder |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 34 |
| Complexity | 699 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | 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 |
| InChi Key | BMXALUHUEGRRCH-JIDHJSLPSA-N |
| InChi Code | 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 |
| Chemical Name | 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 |
| Synonyms | 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; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
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. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CRF1 receptor |
| ln Vitro | 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. |
| ln Vivo |
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.
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] |
| Animal Protocol | 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]. |
| ADME/Pharmacokinetics |
Absorption In adult patients at steady-state, the AUC0-24h and Cmax of crinecerfont were 72846 ng*h/mL and 4231 ng/mL, respectively. In pediatric patients at steady-state, the AUC0-24h ranged from 47062 to 74693 ng*h/mL and the Cmax ranged from 2887 to 4555 ng/mL, depending on the administered dose. The median time to Cmax (i.e. Tmax) is four hours. Route of Elimination Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% of the dose was recovered in feces (2.7% as unchanged parent drug) and 2% in urine (undetectable levels of unchanged parent drug). Volume of Distribution The mean apparent volume of distribution of crinecerfont in adults is 852 liters. Clearance The apparent clearance of crinecerfont is 3.5 L/h. Protein Binding Crinecerfont is highly (≥99.9%) protein bound in plasma. Metabolism / Metabolites _In vitro_, crinecerfont is primarily metabolized by CYP3A4 and to a lesser extent CYP2B6. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism. Biological Half-Life The effective half-life of crinecerfont is approximately 14 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In registration clinical trials, liver test abnormalities were infrequent during crinecerfont therapy and no more common than with placebo. There were no instances of ALT or AST elevations above 3 times the upper limit of normal (ULN) and no cases of liver injury with jaundice or symptoms. Clinical experience with crinecerfont therapy has been limited, but there have no published reports of clinical apparent liver injury with its use. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of crinecerfont during breastfeeding. Because crinecerfont is more than 99% bound to plasma proteins, amounts in milk are likely to be low. If a mother requires crinecerfont, it is not a reason to discontinue breastfeeding. Breastfed infants should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References |
[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. |
| Additional Infomation |
SSR 125543 is an amine. Drug Indication Treatment of atypical haemolytic uremic syndrome, Treatment of paroxysmal nocturnal haemoglobinuria Treatment of congenital adrenal hyperplasia Drug Indication Crinecerfont is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients ≥4 years of age with classic congenital adrenal hyperplasia (CAH). Treatment of atypical haemolytic uremic syndrome, Treatment of paroxysmal nocturnal haemoglobinuria LiverTox Summary Crinecerfont is small molecule inhibitor of the corticotropin releasing factor receptor which is used to treat patients with congenital adrenal hyperplasia. Crinecerfont is has not been associated with significant elevations in serum aminotransferase levels during therapy or with instances of clinically apparent liver injury. Patients with congenital adrenal hyperplasia (CAH) face two major problems: adrenal insufficiency, caused by insufficient endogenous cortisol production, and androgen excess, caused by a counter-regulatory overproduction of adrenocorticotropic hormone (ACTH) from the pituitary. Standard therapy involves cortisol replacement, but typically requires supraphysiological glucocorticoid doses to lower both ACTH and adrenal androgens, resulting in chronic glucocorticoid overexposure. The majority of the poor health outcomes in patients with CAH result from the inability to precisely titrate glucocorticoid dosages to both adequately replace the deficiency and sufficiently attenuate excessive androgen production. Crinecerfont is a selective antagonist of corticotropin-releasing factor (CRF) type 1 receptor that works to reduce excessive ACTH secretion from the pituitary. When administered alongside glucocorticoid replacement in patients with CAH it allows for the use of lower, physiological doses for glucocorticoid replacement, thereby reducing the risks associated with glucocorticoid overexposure. Crinecerfont was approved by the FDA in December 2024 as an adjunct to glucocorticoid replacement in patients with CAH. Crinecerfont is a Corticotropin-releasing Factor Type 1 Receptor Antagonist. The mechanism of action of crinecerfont is as a Corticotropin-releasing Factor Type 1 Receptor Antagonist. Crinecerfont is small molecule inhibitor of the corticotropin releasing factor receptor which is used to treat patients with congenital adrenal hyperplasia. Crinecerfont is has not been associated with significant elevations in serum aminotransferase levels during therapy or with instances of clinically apparent liver injury. CRINECERFONT is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for congenital adrenal hyperplasia and has 1 investigational indication. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~192.49 mM) |
| Solubility (In Vivo) |
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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9249 mL | 9.6246 mL | 19.2493 mL | |
| 5 mM | 0.3850 mL | 1.9249 mL | 3.8499 mL | |
| 10 mM | 0.1925 mL | 0.9625 mL | 1.9249 mL |