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| Targets |
The primary target of LEI-401 is N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme in the biosynthesis of N-acylethanolamines (NAEs), including the endocannabinoid anandamide. LEI-401 is a selective and potent NAPE-PLD inhibitor with an IC50 of 27 nM. By inhibiting NAPE-PLD, the compound reduces the production of NAEs, thereby modulating endocannabinoid signaling. It is a brain-penetrant compound that can be used to study the physiological roles of NAEs.
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| ln Vitro |
In neural cells, LEI-401 decreases a variety of NAEs, including anandamide, in a way that is dependent on NAPE-PLD. With an IC50 of 0.86 μM, LEI-401 (0.04 – 20 μM; 30 min) dose-dependently decreased NAPE-PLD staining in hNAPE-transfected HEK293T cells. In Neuro-2a cells, LEI-401 lowers NAE levels, but not in NAPE-PLD KO cells [1].
In vitro, LEI-401 inhibits NAPE-PLD activity. In HEK293T cells transfected with hNAPE-PLD, LEI-401 (0.04-20 μM; 30 minutes) dose-dependently reduces NAPE-PLD labeling with an IC50 of 0.86 μM. The compound also reduces NAE levels in Neuro-2a cells, but not in NAPE-PLD knockout cells, confirming its on-target activity. |
| ln Vivo |
In mice, LEI-401 (30 mg/kg; i.p.) decreases fear extinction[1]. Moreover, HPA axis signaling is activated by LEI-401[1]. t1/2, Cmax, tmax, AUClast, and F values of 2.5 hours, 1370 ng/mL, 2 hours, 6760 h*ng/mL, and 25%, respectively, were observed with LEI-401 (10 mg/kg; po) treatment[1]. Cmax, tmax, AUClast, and F values for LEI-401 (30 mg/kg; ip) dosing were 10,300 ng/mL, 1 hour, 38,600 h*ng/mL, and 48%, respectively[1].
In vivo, LEI-401 is a potent and effective NAPE-PLD inhibitor. In C57BL/6J mice, LEI-401 reduces the levels of N-acylethanolamines (NAEs) in the brain and modulates emotional behavior. It has been shown to impair fear extinction. These studies demonstrate the compound's utility for probing the physiological roles of the NAPE-PLD pathway. |
| Enzyme Assay |
In vitro enzyme assays for LEI-401 involve measuring the inhibition of NAPE-PLD activity. The enzyme is incubated with a suitable substrate in the presence of varying concentrations of the compound. The production of N-acylethanolamines is measured, and the IC50 value is determined from the concentration-response curve.
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| Cell Assay |
Cellular assays for LEI-401 are performed using cell lines such as HEK293T cells transfected with hNAPE-PLD or Neuro-2a cells. Cells are treated with the compound, and the levels of NAPE-PLD labeling or NAEs are measured. These assays confirm the compound's cellular activity and selectivity.
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| Animal Protocol |
Animal/Disease Models: Male 7–12weeks old C57BL/6J mice[1]
Doses: 30 mg/kg Route of Administration: Ip Experimental Results: Produced a significant increase in freezing as compared to vehicle. Animal/Disease Models: C57BL/6J mice[1] Doses: 10 mg/kg Route of Administration: Po (pharmacokinetic/PK Analysis) Experimental Results: The t1/2, Cmax, tmax, AUClast, and F values were 2.5 hrs (hours), 1370 ng/mL, 2 hrs (hours), 6760 h*ng/mL, and 25 %, respectively. In vivo animal studies for LEI-401 have been conducted in C57BL/6J mice. The compound can be administered via intraperitoneal (i.p.), oral (p.o.), or intravenous (i.v.) routes. Following treatment, brain and plasma levels of NAEs are measured, and behavioral assays (e.g., fear extinction) are performed to assess the functional consequences of NAPE-PLD inhibition. |
| ADME/Pharmacokinetics |
LEI-401 has a molecular weight of 421.54 and a molecular formula of C24H31N5O2. It is soluble in DMSO at 80 mg/mL (189.78 mM). It is typically stored at low temperature as a powder at -20°C for up to 3 years or in solution at -80°C for up to 1 year. Pharmacokinetic studies in mice have been performed for various routes of administration.
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| Toxicity/Toxicokinetics |
There is no specific toxicity data reported for LEI-401 in the available literature. As a research chemical, it should be handled with standard safety precautions. It is not approved for human therapeutic use.
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| References | |
| Additional Infomation |
LEI-401 is a first-in-class, selective, and brain-penetrant NAPE-PLD inhibitor with an IC50 of 27 nM. It has a molecular formula of C24H31N5O2 and a molecular weight of 421.54. It reduces brain NAE levels and modulates emotional behavior in mice.
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| Molecular Formula |
C20H15BRN4O
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| Molecular Weight |
407.263303041458
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| Exact Mass |
421.247
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| CAS # |
2393840-15-6
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| PubChem CID |
145998143
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
609
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| Defined Atom Stereocenter Count |
2
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| SMILES |
BrC1C=CC=CC=1N1C(C)=C(C(NC2C=CC3C=CC=CC=3N=2)=O)C=N1
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| InChi Key |
GFHJYPQZBBHOCC-UXHICEINSA-N
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| InChi Code |
InChI=1S/C24H31N5O2/c30-20-10-12-28(16-20)22-13-21(23(31)25-14-17-8-9-17)26-24(27-22)29-11-4-7-19(15-29)18-5-2-1-3-6-18/h1-3,5-6,13,17,19-20,30H,4,7-12,14-16H2,(H,25,31)/t19-,20+/m1/s1
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| Chemical Name |
N-(cyclopropylmethyl)-6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[(3S)-3-phenylpiperidin-1-yl]pyrimidine-4-carboxamide
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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: 100 mg/mL (237.23 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.93 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 | 2.4554 mL | 12.2772 mL | 24.5543 mL | |
| 5 mM | 0.4911 mL | 2.4554 mL | 4.9109 mL | |
| 10 mM | 0.2455 mL | 1.2277 mL | 2.4554 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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