(R)-Crinecerfont is the R-isomer of Crinecerfont. Crinecerfont (SSR-125543) is a potent, orally active, non-peptide CRF1 receptor antagonist. Crinecerfont can be used in the study of congenital adrenal hyperplasia (CAH). Crinecerfont is a click chemistry reagent that contains an alkynyl group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing an alkynyl group.

Physicochemical Properties

Molecular Formula	C27H28CLFN2OS
Molecular Weight	483.04
Exact Mass	483.04
Elemental Analysis	C, 67.14; H, 5.84; Cl, 7.34; F, 3.93; N, 5.80; O, 3.31; S, 6.64
CAS #	2649012-21-3
Related CAS #	321839-75-2; 752253-39-7
Appearance	Typically exists as solids at room temperature
LogP	8
SMILES	S1C(C)=C(C2=CC(C)=C(OC)C=C2Cl)N=C1N([C@@H](C1=CC=C(C)C(F)=C1)CC1CC1)CC#C
InChi Key	IEAKXXNRGSLYTQ-XMMPIXPASA-N
InChi Code	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-/m1/s1
Chemical Name	4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine
Synonyms	(R)-SSR-125543; 2649012-21-3; (R)-Crinecerfont; 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1A)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine; orb1689817; SCHEMBL23458452;
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
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 Vivo	Context: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. Objective: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. Methods: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. Conclusion: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.[1]
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]. Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2023 Oct 18;108(11):2871-2878.

Solubility Data

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

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 (e.g. IP/IV/IM/SC) 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). 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) 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). 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 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.0702 mL	10.3511 mL	20.7022 mL
	5 mM	0.4140 mL	2.0702 mL	4.1404 mL
	10 mM	0.2070 mL	1.0351 mL	2.0702 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.