| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| 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, 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. |
| Toxicity/Toxicokinetics |
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. |
| References |
| 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)
|
| 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
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.) |
| 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.
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.
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