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| Targets |
NBI-27914 targets the corticotropin-releasing factor receptor 1 (CRFR1), a G protein-coupled receptor that is a member of the CRF receptor family. CRFR1 is activated by corticotropin-releasing factor (CRF) and plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the stress response. By selectively antagonizing CRFR1, NBI-27914 blocks CRF-mediated signaling, reducing the stress response and modulating anxiety, depression, and other stress-related disorders. The compound's selectivity for CRFR1 over CRFR2 makes it a valuable tool for studying CRFR1 function and for developing novel therapeutics for stress-related disorders.
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| ln Vitro |
In vitro, NBI-27914 acts as a potent and selective antagonist of CRFR1. In cell-based assays, the compound blocks CRF-induced activation of CRFR1, as measured by inhibition of cAMP production or calcium mobilization. Its activity is concentration-dependent, with effective concentrations in the nanomolar range. The compound's selectivity for CRFR1 over CRFR2 supports its use as a specific probe for CRFR1 function. It has been used to study the effects of CRFR1 antagonism on steroidogenic gene expression in GD15 mouse testis. Detailed IC50 values are available in published literature.
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| ln Vivo |
In vivo, NBI-27914 has been studied in animal models of anxiety, depression, and stress-related disorders. Administration of the compound reduces anxiety-like behaviors and stress responses in rodent models. Its ability to block CRFR1-mediated signaling makes it a valuable tool for studying the role of CRF in stress and affective disorders. The compound is typically administered via intraperitoneal injection in preclinical studies. Its efficacy in reducing stress-related behaviors supports its potential as a therapeutic for anxiety, depression, and other stress-related disorders. However, detailed pharmacokinetic profiles and comprehensive toxicology data are limited in publicly available sources.
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| Enzyme Assay |
The in vitro CRFR1 antagonist assay for NBI-27914 typically uses cells expressing recombinant human CRFR1 (e.g., CHO or HEK293 cells). The assay is performed in 96-well or 384-well plates using a cAMP assay (e.g., HTRF or ELISA-based) or a calcium mobilization assay (using Fluo-4 or other calcium-sensitive dyes). Cells are treated with varying concentrations of the test compound (typically 0.01 nM to 10 µM) and stimulated with CRF or a CRFR1 agonist. The inhibition of cAMP reduction or calcium flux is measured, and IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against CRFR2 and other GPCRs. Positive controls (e.g., known CRFR1 antagonists) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cells expressing CRFR1 or primary cells (e.g., pituitary cells) are treated with NBI-27914 at concentrations ranging from 0.01 nM to 10 µM for 1-24 hours, followed by stimulation with CRF. cAMP levels are measured by ELISA or HTRF. Downstream signaling is assessed by measuring phosphorylation of CREB or other signaling proteins by Western blotting. Cell viability is assessed using MTT or CellTiter-Glo assays. For steroidogenic studies, testicular or adrenal cells are treated with the compound, and steroid hormone production is measured by ELISA or RIA. All experiments include appropriate controls (vehicle, known CRFR1 antagonists) and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, rodent models of anxiety (e.g., elevated plus maze, open field test, light-dark box), depression (e.g., forced swim test, tail suspension test), or stress (e.g., restraint stress, chronic mild stress) are used. NBI-27914 is administered intraperitoneally or orally at doses ranging from 1 to 30 mg/kg, typically 30-60 minutes before behavioral testing. Stress-induced corticosterone levels are measured in blood by ELISA or RIA. Brain tissue is collected for analysis of CRF and CRFR1 expression. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of NBI-27914 have been partially characterized. The compound has a molecular weight of 434.19 and a molecular formula of C18H20Cl4N4. Following intraperitoneal administration, the compound shows moderate absorption with a Tmax of 0.5-2 hours. Plasma half-life is estimated to be 2-4 hours. The compound distributes into tissues including brain, consistent with its central nervous system activity. Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion. Oral bioavailability is limited due to first-pass metabolism. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of NBI-27914 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 30 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
5-Chloro-N4-(cyclopropylmethyl)-2-methyl-N4-propyl-N6-(2,4,6-trichlorophenyl)pyrimidine-4,6-diamine is a dialkyl aromatic amine and also a tertiary amine compound.
NBI-27914 is a potent and selective CRFR1 antagonist used to study stress-related disorders such as anxiety and depression. It has a molecular formula of C18H20Cl4N4 and a molecular weight of 434.19. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent (≥98%) for laboratory use only. Its selective antagonism of CRFR1 makes it a valuable tool for studying CRF signaling, stress responses, and for developing novel therapeutics for stress-related disorders. |
| Molecular Formula |
C18H20N4CL4
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| Molecular Weight |
434.1902
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| Exact Mass |
468.021
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| CAS # |
184241-44-9
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| Related CAS # |
NBI-27914 hydrochloride;1215766-76-9
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| PubChem CID |
176157
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.417g/cm3
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| Boiling Point |
483.7ºC at 760mmHg
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| Flash Point |
246.3ºC
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| Vapour Pressure |
1.64E-09mmHg at 25°C
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| Index of Refraction |
1.649
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| LogP |
7.643
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
26
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| Complexity |
441
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCN(CC1CC1)C2=NC(=NC(=C2Cl)NC3=C(C=C(C=C3Cl)Cl)Cl)C.Cl
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| InChi Key |
KNADXBVKFAUMCR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H20Cl4N4/c1-3-6-26(9-11-4-5-11)18-15(22)17(23-10(2)24-18)25-16-13(20)7-12(19)8-14(16)21/h7-8,11H,3-6,9H2,1-2H3,(H,23,24,25)
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| Chemical Name |
5-chloro-4-N-(cyclopropylmethyl)-2-methyl-4-N-propyl-6-N-(2,4,6-trichlorophenyl)pyrimidine-4,6-diamine
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| HS Tariff Code |
2934.99.9001
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| 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, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~230.31 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1 mg/mL (2.30 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: 1 mg/mL (2.30 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3031 mL | 11.5157 mL | 23.0314 mL | |
| 5 mM | 0.4606 mL | 2.3031 mL | 4.6063 mL | |
| 10 mM | 0.2303 mL | 1.1516 mL | 2.3031 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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