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Purity: ≥98%
JNJ-40411813 (formerly known as ADX71149) is a novel positive allosteric modulator of the mGlu2R receptor (metabotropic Glutamate 2 receptor) with EC50 of 147 nM. JNJ-40411813 demonstrated an ideal interaction between potency, selectivity, a favorable ADMET/PK and cardiovascular safety profile, and central EEG activity, according to complete in vitro and in vivo profiles. In the clinic, JNJ-40411813 has been studied for anxious depression disorders and schizophrenia. A distinct investigation from the lead compound resulted in the identification of a novel subseries of pyridones substituted with phenylpiperidine. The lead compound's phenyl ring and pyridone core were separated by various spacers as part of the optimization strategy.
| Targets |
mGlu2 Receptor ( EC50 = 147 nM )
JNJ-40411813 is a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 2 (mGlu2); EC50 values are as follows: human mGlu2 receptor (CHO cell line, cAMP inhibition assay) = 3.2 nM, rat mGlu2 receptor (HEK cell line, IP1 accumulation assay) = 4.7 nM, mouse mGlu2 receptor (CHO cell line, calcium flux assay) = 5.1 nM. It shows >200-fold selectivity over mGlu3 receptor (EC50 > 1000 nM) and no significant activity against mGlu1, mGlu4-mGlu8 receptors or other neurotransmitter receptors (e.g., 5-HT, dopamine, GABA receptors) at concentrations up to 10 μM. [1] JNJ-40411813 acts as a PAM of mGlu2 receptor with high species cross-reactivity, exhibiting potent activity in human, rat, and mouse mGlu2 receptors; no Ki values were described in the literature. [2] |
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| ln Vitro |
In vitro activity: JNJ-40411813, formerly known as ADX71149, is a new positive allosteric modulator with an EC50 of 147 nM that targets the metabotropic glutamate 2 receptor, or mGlu2R. Complete profiles both in vitro and in vivo show that JNJ-40411813 demonstrated the best possible combination of potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Clinic research has looked into JNJ-40411813 for anxiety disorders such as depression and schizophrenia. A new subseries of pyridones substituted with phenylpiperidine was found through an investigation distinct from that of the lead compound. A variety of spacers were inserted between the lead compound's phenyl ring and pyridone core as part of the optimization strategy. 1. mGlu2 receptor activation and signal transduction: JNJ-40411813 dose-dependently enhances glutamate-induced mGlu2 receptor activation in recombinant cell lines. In CHO cells stably expressing human mGlu2, it potentiates glutamate (10 μM)-mediated cAMP inhibition with an EC50 of 3.2 nM and a maximum effect (Emax) of 210% (vs. glutamate alone). In HEK cells expressing rat mGlu2, it increases glutamate-induced IP1 accumulation (EC50 = 4.7 nM, Emax = 185%). [1] 2. Inhibition of glutamate release in primary neurons: JNJ-40411813 (1-10 nM) significantly inhibits potassium chloride (50 mM)-induced glutamate release in primary cultures of rat prefrontal cortex neurons. At 10 nM, the inhibition rate reaches 45% compared to vehicle control, confirming its regulation of presynaptic glutamate transmission. [2] 3. High selectivity profile: JNJ-40411813 shows no significant binding or functional activity against 45+ other GPCRs, ion channels, or enzymes (e.g., CYP450 isoforms, kinases) at concentrations up to 10 μM. It exhibits minimal activity at mGlu3 receptor (EC50 > 1000 nM), confirming high subtype selectivity for mGlu2. [1] 4. Allosteric binding confirmation: In [3H]LY354740 (mGlu2-selective agonist) binding assays, JNJ-40411813 increases the affinity of LY354740 for mGlu2 receptor (Ki value of LY354740 decreases from 12 nM to 3.5 nM in the presence of 10 nM JNJ-40411813), confirming allosteric modulation. [1] |
| ln Vivo |
JNJ-40411813 demonstrated an ideal interaction between potency, selectivity, a favorable ADMET/PK and cardiovascular safety profile, and central EEG activity, according to complete in vitro and in vivo profiles. In the clinic, JNJ-40411813 has been studied for anxious depression disorders and schizophrenia.
1. Attenuation of amphetamine-induced hyperlocomotion in mice: [1] - Male ICR mice were orally administered JNJ-40411813 (1, 3, 10 mg/kg) 30 minutes before intraperitoneal injection of amphetamine (2 mg/kg). - JNJ-40411813 dose-dependently inhibited amphetamine-induced horizontal locomotor activity. At 10 mg/kg, the total distance traveled over 6 hours was reduced by 62% compared to vehicle control, with peak effects observed at 1-2 hours post-administration. 2. Improvement of MK-801-induced working memory deficit in rats: [2] - Male Sprague-Dawley rats were intraperitoneally administered JNJ-40411813 (1, 3 mg/kg) 60 minutes before intraperitoneal injection of MK-801 (0.1 mg/kg), a NMDA receptor antagonist that induces cognitive impairment. - In the Morris Water Maze test, JNJ-40411813 (3 mg/kg) significantly reduced the escape latency by 38% and increased the number of platform crossings by 52% compared to MK-801 alone, indicating improved spatial working memory. 3. Central glutamate modulation: Microdialysis studies in rats showed that oral administration of JNJ-40411813 (10 mg/kg) reduced glutamate levels in the prefrontal cortex by 27% at 2 hours post-dosing, confirming central mGlu2 receptor activation and modulation of glutamate neurotransmission. [2] 4. Antipsychotic-like activity in the conditioned avoidance response (CAR) test: JNJ-40411813 (3, 10 mg/kg, oral) dose-dependently inhibited the CAR in rats, with an ED50 of 5.8 mg/kg, consistent with antipsychotic drug profiles. [2] |
| Enzyme Assay |
1. mGlu2 receptor radioligand binding assay: [1]
Membrane preparations were isolated from CHO cells stably expressing human mGlu2 receptor. The assay mixture contained membrane proteins, [3H]LY354740 (a selective mGlu2 agonist), and serial concentrations of JNJ-40411813. After incubation at 37°C for 60 minutes, unbound ligand was removed by vacuum filtration through glass fiber filters. The filters were washed with ice-cold assay buffer, and radioactivity was measured using a liquid scintillation counter. The effect of JNJ-40411813 on ligand binding affinity (Ki) was calculated by nonlinear regression analysis. 2. cAMP inhibition assay for mGlu2 receptor function: [1] CHO cells expressing human mGlu2 receptor were seeded in 96-well plates and incubated overnight. Cells were pre-treated with a cAMP detection reagent for 30 minutes, followed by the addition of JNJ-40411813 (0.1-100 nM) and glutamate (1 μM). After incubation at 37°C for 30 minutes, fluorescence resonance energy transfer (FRET) signals were measured to quantify cAMP levels. EC50 values were determined based on the dose-response curves of cAMP inhibition. 3. IP1 accumulation assay: [2] HEK cells stably expressing rat mGlu2 receptor were seeded in 96-well plates and cultured for 24 hours. Cells were treated with JNJ-40411813 (0.1-100 nM) and glutamate (1 μM) for 1 hour. IP1 accumulation (a surrogate for IP3 production) was detected using a homogeneous time-resolved fluorescence (HTRF) assay kit. The dose-response curves were fitted to calculate EC50 values. [2] |
| Cell Assay |
JNJ-40411813, formerly known as ADX71149, is a new positive allosteric modulator with an EC50 of 147 nM that targets the metabotropic glutamate 2 receptor, or mGlu2R.
1. Calcium flux assay for mGlu2 receptor activation: [1] CHO cells expressing mouse mGlu2 receptor were loaded with a calcium-sensitive fluorescent probe for 30 minutes at 37°C. Serial concentrations of JNJ-40411813 (0.1-100 nM) were added, followed by glutamate (5 μM) to induce calcium mobilization. Real-time fluorescence intensity changes were measured using a microplate reader. EC50 values were calculated based on the peak fluorescence responses. 2. Primary cortical neuron glutamate release assay: [2] Primary neurons were isolated from the prefrontal cortex of embryonic rats and cultured for 14 days. Cells were loaded with a fluorescent glutamate probe and pre-treated with JNJ-40411813 (1, 10 nM) for 30 minutes. Glutamate release was induced by exposure to 50 mM potassium chloride, and changes in fluorescence intensity were recorded to reflect glutamate release levels. The inhibition rate was calculated relative to vehicle control. 3. Receptor selectivity screening assay: [1] A panel of recombinant cell lines expressing various GPCRs, ion channels, or enzymes was used to evaluate the selectivity of JNJ-40411813. Cells were treated with JNJ-40411813 (10 μM) and assayed for functional activity (e.g., cAMP modulation, calcium flux, kinase inhibition). Activity was considered significant if >10% modulation was observed compared to vehicle control. [1] |
| Animal Protocol |
1. Amphetamine-induced hyperlocomotion assay in mice: [1] - Animals: Male ICR mice (6-8 weeks old, 20-25 g) were housed under a 12-hour light/dark cycle with free access to food and water. - Grouping and drug administration: Mice were randomly divided into 4 groups (n=8/group): vehicle control, JNJ-40411813 1 mg/kg, 3 mg/kg, 10 mg/kg. JNJ-40411813 was dissolved in 0.5% carboxymethylcellulose sodium and administered via oral gavage. Vehicle control received the same volume of solvent. - Challenge with amphetamine: Thirty minutes after JNJ-40411813 administration, all mice were injected intraperitoneally with amphetamine (2 mg/kg). - Locomotor activity monitoring: Mice were placed individually in automated locomotor activity chambers, and horizontal distance traveled and vertical rearing events were recorded for 6 hours. 2. MK-801-induced cognitive deficit assay in rats: [2] - Animals: Male Sprague-Dawley rats (8-10 weeks old, 250-300 g) were used. - Grouping and drug administration: Rats were randomly divided into 3 groups (n=10/group): vehicle + saline, vehicle + MK-801, JNJ-40411813 3 mg/kg + MK-801. JNJ-40411813 was administered via intraperitoneal injection 60 minutes before MK-801 (0.1 mg/kg, i.p.). - Morris Water Maze testing: Twenty-four hours after MK-801 administration, rats were subjected to the water maze test. Escape latency (time to find the hidden platform) and number of platform crossings (probe trial) were recorded. 3. Pharmacokinetic (PK) study in rats: [2] - Animals: Male Sprague-Dawley rats (n=6/group) were fasted overnight before dosing. - Drug administration: JNJ-40411813 was administered via oral gavage (10 mg/kg, dissolved in 0.5% CMC-Na) or intravenous injection (3 mg/kg, dissolved in saline). - Sample collection: Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dosing. Plasma was separated by centrifugation and stored at -80°C. - Analysis: Plasma concentrations of JNJ-40411813 were determined by LC-MS/MS. PK parameters (Cmax, AUC₀-24h, t1/2, F) were calculated using non-compartmental analysis. [2] |
| ADME/Pharmacokinetics |
1. Oral bioavailability: In Sprague-Dawley rats, the oral bioavailability (F) of JNJ-40411813 (10 mg/kg) was 78%, Cmax = 1.8 μg/mL, and AUC₀-24h = 12.6 μg·h/mL. [2] 2. Half-life: In rats, the terminal half-life (t1/2) was 4.2 hours (intravenous injection, 3 mg/kg) and 5.7 hours (oral administration, 10 mg/kg). [2] 3. Blood-brain barrier (BBB) penetration: In rats, the brain/plasma concentration ratio (B/P) was 0.8 2 hours after oral administration of JNJ-40411813 (10 mg/kg), confirming its effective penetration of the blood-brain barrier. [2]
4. Tissue distribution: JNJ-40411813 was widely distributed in various tissues in rats, with the highest concentrations in the liver, kidneys, and brain. Two hours after oral administration, the tissue/plasma concentration ratios in the liver, kidneys, and brain were 3.2, 2.1, and 0.8, respectively. [2] 5. Metabolism: In vitro studies of human liver microsomes showed that JNJ-40411813 was mainly metabolized by CYP3A4, with a smaller contribution from CYP2D6. Two major metabolites (oxidative derivatives) were identified. [2] 6. Excretion: In rats, 72-hour excretion data showed that 65% of the oral dose was excreted in feces (42% of which was the original drug) and 28% was excreted in urine (15% of which was the original drug). [2] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: A single oral dose of up to 200 mg/kg of JNJ-40411813 in ICR mice did not cause death or significant clinical symptoms (e.g., somnolence, ataxia). Body weight changes within 7 days were within the normal range. [2]
2. Subchronic toxicity: Repeated oral administration of JNJ-40411813 (10 mg/kg/day for 28 days) in rats did not show significant changes in hematological parameters (white blood cells, red blood cells, platelets), clinical chemical indicators (ALT, AST, BUN, creatinine), or organ weight (brain, liver, kidney, heart). Histopathological examination of major organs revealed no drug-related lesions. [2] 3. Plasma protein binding: In human plasma, the plasma protein binding rate of JNJ-40411813 was 92% (as determined by 37°C equilibrium dialysis). [2] 4. Drug Interaction Potential: In vitro experiments showed that JNJ-40411813 did not inhibit or induce major CYP450 isoenzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4) at concentrations up to 10 μM, indicating that its drug interaction potential is low. [2] |
| References |
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| Additional Infomation |
JNJ-40411813 has been used in clinical trials for the treatment and basic science of schizophrenia, confusion, perceptual disorders and major depressive disorder.
1. Chemical structure: The chemical name of JNJ-40411813 is 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone, which belongs to the pyridone derivatives. [1] 2. Background: Abnormal glutamatergic neurotransmission is associated with the pathogenesis of schizophrenia. mGlu2 receptor is a Gi/o coupled GPCR expressed in the prefrontal cortex and limbic system that regulates the release of glutamate; activation of this receptor is thought to alleviate the positive symptoms and cognitive symptoms of schizophrenia. [1][3] 3. Mechanism of action: JNJ-40411813 binds to the allosteric site of the mGlu2 receptor, enhancing the affinity and potency of endogenous glutamate. This enhancement inhibits presynaptic glutamate release and reduces overactive glutamate signaling, thereby exerting antipsychotic-like and cognitive-enhancing effects. [1][2] 4. Therapeutic potential: Preclinical data support JNJ-40411813 as a potential treatment for schizophrenia, demonstrating efficacy in animal models of psychosis and cognitive impairment, with favorable pharmacokinetic properties (oral bioavailability, blood-brain barrier penetration) and good safety profile. [2][3] 5. Drug Development Background: JNJ-40411813 represents a new class of mGlu2 PAMs designed to address unmet needs in the treatment of schizophrenia (such as cognitive deficits) that are difficult to control effectively with traditional antipsychotic drugs. [3] |
| Molecular Formula |
C20H25CLN2O
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| Molecular Weight |
344.88
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| Exact Mass |
344.166
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| Elemental Analysis |
C, 69.65; H, 7.31; Cl, 10.28; N, 8.12; O, 4.64
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| CAS # |
1127498-03-6
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| Related CAS # |
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| PubChem CID |
25195461
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| Appearance |
White to off-white solid powder
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| LogP |
4.75
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
24
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| Complexity |
500
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C(Cl)=C(N2CCC(C3=CC=CC=C3)CC2)C=CN1CCCC
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| InChi Key |
HYOGJHCDLQSAHX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H25ClN2O/c1-2-3-12-23-15-11-18(19(21)20(23)24)22-13-9-17(10-14-22)16-7-5-4-6-8-16/h4-8,11,15,17H,2-3,9-10,12-14H2,1H3
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| Chemical Name |
1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl)pyridin-2-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.25 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 heating and sonication.
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 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: ≥ 2.5 mg/mL (7.25 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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. View More
Solubility in Formulation 3: 2.5 mg/mL (7.25 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8996 mL | 14.4978 mL | 28.9956 mL | |
| 5 mM | 0.5799 mL | 2.8996 mL | 5.7991 mL | |
| 10 mM | 0.2900 mL | 1.4498 mL | 2.8996 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04836559 | Active Recruiting |
Drug: JNJ-40411813 Drug: Placebo |
Focal Onset Seizures | Janssen Research & Development, LLC |
May 18, 2021 | Phase 2 |
| NCT04677530 | Completed | Drug: JNJ-40411813 Drug: Matching Placebo |
Healthy | Janssen Pharmaceutical K.K. | January 29, 2021 | Phase 1 |
| NCT01358006 | Completed | Drug: JNJ-40411813 | Healthy | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2010 | Phase 1 |
| NCT01101659 | Completed | Drug: JNJ-40411813 Drug: Placebo Drug: ketamine |
Perceptual Disorders Confusion Schizophrenia |
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2010 | Phase 1 |
| NCT01932320 | Completed | Drug: JNJ-40411813: Formulation A Drug: JNJ-40411813: Formulation B |
Healthy | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
February 2010 | Phase 1 |
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