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| 1mg |
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| 5mg |
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| Targets |
NF-1819 targets monoacylglycerol lipase (MGL/MAGL), a key enzyme responsible for hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG). By irreversibly inhibiting MGL, NF-1819 increases 2-AG levels in the brain, thereby enhancing endocannabinoid signaling. This mechanism underlies its therapeutic potential in neuroinflammatory and pain conditions. The compound is selective for MGL over other serine hydrolases.
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| ln Vitro |
In vitro, NF-1819 acts as an irreversible inhibitor of MGL, covalently binding to the enzyme's active site serine residue. The compound demonstrates potent inhibitory activity in biochemical assays using recombinant MGL enzyme. It shows high selectivity for MGL over other related serine hydrolases. The compound's membrane permeability facilitates its uptake into cells for target engagement studies. Detailed IC₅₀ values and kinetic parameters are available in the primary literature.
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| ln Vivo |
In vivo, NF-1819 alleviates disease symptoms in multiple sclerosis (MS) models and exhibits analgesic effects in acute inflammatory pain models. The compound ameliorates neuropathic hypersensitivity induced by oxaliplatin. Its efficacy is attributed to increased 2-AG levels in the central nervous system following MGL inhibition. The compound's BBB penetration enables central target engagement after systemic administration. Dosing regimens and administration routes are described in preclinical pharmacology studies.
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| Enzyme Assay |
In vitro enzyme inhibition assays for NF-1819 typically use purified recombinant human MGL enzyme and a fluorogenic substrate (e.g., 4-nitrophenyl acetate or arachidonoyl-7-hydroxy-6-methoxy-4-methylcoumarin ester). The compound is dissolved in DMSO and serially diluted in assay buffer (50 mM Tris-HCl, pH 7.4, 0.1% Triton X-100). Enzyme and inhibitor are pre-incubated for 5-30 minutes at 25°C to allow irreversible binding, followed by substrate addition. Fluorescence (excitation 340 nm, emission 460 nm) is monitored continuously. IC₅₀ values and inactivation rates (kinact/KI) are calculated.
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| Cell Assay |
For cell-based assays, relevant cell lines (e.g., Neuro2a or primary neurons) are cultured in DMEM with 10% FBS. Cells are seeded in 96-well plates and treated with NF-1819 at various concentrations (0.001-10 μM) for 1-24 hours. MGL activity in cell lysates is measured using fluorogenic substrate. 2-AG levels are quantified by LC-MS/MS to confirm target engagement. Cell viability is assessed by MTT or ATP-lite assays. Western blotting may be used to confirm MGL expression and compound binding. All treatments include vehicle controls and are performed in triplicate.
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| Animal Protocol |
In vivo, NF-1819 is typically administered to rodents via intraperitoneal (IP) or oral gavage. For MS models (e.g., experimental autoimmune encephalomyelitis, EAE), compound is dosed daily at 1-10 mg/kg starting at disease onset. For pain models, a single dose (3-30 mg/kg) is administered prior to testing. Endpoints include clinical scoring (EAE), paw withdrawal thresholds (mechanical allodynia), and tail flick latencies (thermal hyperalgesia). Brain and spinal cord tissues are collected for 2-AG measurement and MGL activity assays. Plasma and brain concentrations are determined by LC-MS/MS for PK/PD correlation.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for NF-1819 indicate high membrane permeability and BBB penetration. The compound is expected to have good oral bioavailability based on its lipophilic nature. It is likely metabolized by hepatic cytochrome P450 enzymes. Plasma protein binding is predicted to be moderate to high. The compound's brain-to-plasma ratio suggests efficient central nervous system distribution. Further detailed ADME parameters (half-life, clearance, volume of distribution) are available in preclinical study reports.
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| Toxicity/Toxicokinetics |
Toxicology data for NF-1819 are limited in publicly available sources. Based on its mechanism as an irreversible enzyme inhibitor, potential off-target effects on other serine hydrolases should be considered. In preclinical studies, the compound was tolerated at efficacious doses without significant adverse events reported. Standard safety pharmacology and toxicology studies (acute, subchronic, genotoxicity) would be required for therapeutic development. The compound is for research use only and not intended for human therapeutic applications.
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| References | |
| Additional Infomation |
NF-1819 (also known as MGL-IN-1) is a research-grade chemical probe for studying the endocannabinoid system. Its primary applications include neuroinflammation, pain, and multiple sclerosis research. The compound is not approved for clinical use and has not entered clinical trials. Its irreversible mechanism of action provides sustained target inhibition, making it useful for prolonged pharmacological studies. The compound is commercially available from various chemical suppliers for research purposes only. Further medicinal chemistry optimization may yield derivatives with improved selectivity and pharmacokinetic properties.
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| Molecular Formula |
C24H22FN5O4
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|---|---|
| Molecular Weight |
463.4694
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| Exact Mass |
463.165
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| CAS # |
1881244-28-5
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| PubChem CID |
127032456
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
660.5±65.0 °C at 760 mmHg
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| Flash Point |
353.2±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.735
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| LogP |
1.14
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
34
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| Complexity |
773
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1CN(CCC1N2[C@@H]([C@H](C2=O)C3=CC=C(C=C3)F)C4=CC5=C(C=C4)OCO5)C(=O)N6C=NC=N6
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| InChi Key |
XRIROGBLGLPXQI-FGZHOGPDSA-N
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| InChi Code |
InChI=1S/C24H22FN5O4/c25-17-4-1-15(2-5-17)21-22(16-3-6-19-20(11-16)34-14-33-19)30(23(21)31)18-7-9-28(10-8-18)24(32)29-13-26-12-27-29/h1-6,11-13,18,21-22H,7-10,14H2/t21-,22-/m1/s1
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| Chemical Name |
(3R,4S)-4-(1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)-1-[1-(1,2,4-triazole-1-carbonyl)piperidin-4-yl]azetidin-2-one
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| Synonyms |
NF1819; NF 1819; NF-1819
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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 |
| 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 : ~62.5 mg/mL (~134.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.49 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 20.8 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: 2.08 mg/mL (4.49 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1576 mL | 10.7882 mL | 21.5764 mL | |
| 5 mM | 0.4315 mL | 2.1576 mL | 4.3153 mL | |
| 10 mM | 0.2158 mL | 1.0788 mL | 2.1576 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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