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Purity: ≥98%
JNJ-46778212 (also known as VU 0409551) is a novel, potent, orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulator (PAMs) with an EC50 of 260 nM. JNJ-46778212 demonstrates a unique stimulus bias and preferentially enhances mGlu5 coupling to Gαq-mediated signaling in the rat hippocampal regions, but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity. On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, JNJ-46778212 was selected as a candidate for further development.
| Targets |
mGlu5 Receptor ( EC50 = 260 nM )
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|---|---|
| ln Vitro |
In calcium mobilization assay using HEK293 cells expressing human mGlu5, JNJ-46778212 potentiated the response with EC50 = 260 nM and 84% Glu Max[1]
Induced a ~10-fold shift of the glutamate concentration-response curve on human mGlu5 at 10 µM[1] No potentiation of NMDA receptor currents or NMDA receptor-dependent long-term potentiation (LTP) was observed[1] Potentiates DHPG-induced long-term depression (LTD), calcium mobilization, and ERK phosphorylation[1] |
| ln Vivo |
JNJ-46778212 exhibits good CNS penetration in oral brain/plasma studies[1]. In hippocampus slices taken from SR−/− mice, JNJ-46778212 improves NMDAR function and restores long-term potentiation. When SR−/− mice receive JNJ-46778212, their deficits in multiple neuroplasticity signaling pathways are reversed, and their contextual fear memory is improved[2].
JNJ-46778212 reversed amphetamine-induced hyperlocomotion (AHL) in rats with MED = 10 mg/kg po, ED50 = 23 mg/kg po, and maximal reversal ~78% at 100 mg/kg po[1] Also reversed MK-801-induced hyperlocomotion and conditioned avoidance responding (CAR) with ED50 = 65 mg/kg po[1] Increased prefrontal dopamine levels (MED = 10 mg/kg po) without affecting prolactin levels or inducing catalepsy[1] Induced septal eFos mRNA by 153% at 40 mg/kg po[1] Showed efficacy in contextual fear conditioning (CFC) with MED = 1 mg/kg po and novel object recognition with MED = 3 mg/kg po[1] No seizure activity observed in mice at doses >100-fold over AHL MED, and no FJC staining after 4 days at 120 mg/kg po[1] Chronic dosing at 450 mg/kg po for 14 days did not induce seizures in rats[1] |
| Enzyme Assay |
Calcium mobilization assay was performed using HEK293 cells expressing human mGlu5. Cells were loaded with a calcium-sensitive dye, stimulated with an EC20 concentration of glutamate, and JNJ-46778212 was added in increasing concentrations to measure potentiation of calcium response[1]
Radioligand binding assay was conducted using [³H]-mPEPy to determine displacement by JNJ-46778212, confirming MPEP-site binding[1] |
| Cell Assay |
Calcium mobilization assay: HEK293 cells stably expressing human mGlu5 were used to assess PAM activity. Cells were incubated with a calcium-sensitive fluorescent dye, then treated with glutamate (EC20) and varying concentrations of JNJ-46778212. Fluorescence was measured to determine calcium flux[1]
Cytotoxicity assay: A high-content cytotoxicity assay was performed, showing no toxicity at concentrations >30 µM[1] |
| Animal Protocol |
Mice: For five days, SR−/− mice are given intraperitoneal (i.p.) injections of either VU0409551 (10 mL/kg) or a vehicle (20 % hydroxypropyl β-cyclodextran). In the in vivo pharmacokinetic and dose-finding experiments, VU0409551 (10 and 30 mg/kg) or vehicle is administered to WT mice (n = 5–6/dose). WT mice receive vehicle for the SR−/− mice reversal studies, while SR−/− mice receive either vehicle or VU0409551 (30 mg/kg). On day 5, two hours after the last injection, all mice are euthanized[1].
Amphetamine-induced hyperlocomotion (AHL) model: Rats were administered amphetamine to induce hyperlocomotion, followed by oral administration of JNJ-46778212 at doses ranging from 3–566 mg/kg. Locomotor activity was monitored[1] Contextual fear conditioning (CFC) model: Mice were administered JNJ-46778212 orally at 1 mg/kg prior to conditioning, and freezing behavior was assessed during re-exposure to context[1] Novel object recognition test: Mice were treated orally with JNJ-46778212 at 3 mg/kg, and exploration of novel vs. familiar objects was measured[1] Chronic dosing for neurotoxicity assessment: Rats received JNJ-46778212 at 450 mg/kg po daily for 14 days, and seizure activity was monitored[1] |
| ADME/Pharmacokinetics |
Metabolic stability: After 15 minutes of microsomal incubation, 15% (human), 35% (rat) and 26% (dog) of JNJ-46778212 remained [1]. Plasma protein binding: The free fraction (fu) was 3.2% (human), 7% (rat), 24.1% (mouse) and 9.6% (dog) [1]. Brain permeability: The brain-plasma ratio (Kp) was 1.0 (mouse) and 2.3 (rat) [1]. Oral bioavailability: 44% (mouse), 96% (rat), and 51% (dog) [1]. Half-life (t1/2): 16 hours (mice, intravenous injection), 2.5 hours (rat, intravenous injection), and 67 hours (dog, intravenous injection) [1]. Clearance (CL): 39 mL/min/kg (mice), 24 mL/min/kg (rats), 12 mL/min/kg (dogs) [1] Volume of distribution (Vdss): 29 L/kg (mice), 3.3 L/kg (rats), 37 L/kg (dogs) [1]
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| Toxicity/Toxicokinetics |
At concentrations >10 µM, it has no significant inhibitory effect on hERG, Ca2+ or Na+ channels [1]. It is inactive in anesthetized guinea pig and canine cardiovascular models, and has a safety window >80 times [1]. It has a weak binding affinity to MAO-B (Ki = 6.4 µM) [1]. The AMES test, high-content cytotoxicity test (>30 µM) and GSH/CN capture study results were all negative [1]. Long-term high-dose administration (360 mg/kg, orally, for 30 consecutive days) induced Fluoro-Jade C (FJC) staining in a few rats [1].
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| References | |
| Additional Infomation |
JNJ-46778212 is a pure mGlu5 positive allosteric modulator (PAM) without agonist PAM activity and can reduce the risk of seizures [1]. It does not enhance NMDA receptor currents and therefore has signal bias, which may help broaden the therapeutic window [1]. The drug was originally developed for the treatment of schizophrenia and has shown efficacy in both antipsychotic and cognitive areas without increasing prolactin levels or causing rigidity [1]. Although an Investigational New Drug (IND) study has been initiated, progress has been suspended due to neurotoxicity issues associated with long-term high-dose administration [1].
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| Molecular Formula |
C20H17FN2O3
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|---|---|
| Molecular Weight |
352.358988523483
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| Exact Mass |
352.12
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| Elemental Analysis |
C, 68.17; H, 4.86; F, 5.39; N, 7.95; O, 13.62
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| CAS # |
1363281-27-9
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| PubChem CID |
56846694
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
478
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QUZLMKNNIUSREV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H17FN2O3/c21-15-8-6-14(7-9-15)20(24)23-11-10-17-18(12-23)26-19(22-17)13-25-16-4-2-1-3-5-16/h1-9H,10-13H2
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| Chemical Name |
(4-fluorophenyl)-[2-(phenoxymethyl)-6,7-dihydro-4H-[1,3]oxazolo[5,4-c]pyridin-5-yl]methanone
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| Synonyms |
JNJ-46778212; JNJ 46778212; JNJ46778212; VU0409551; VU-0409551; VU 0409551
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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 (~283.8 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.90 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 (5.90 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 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 (5.90 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 | 2.8380 mL | 14.1900 mL | 28.3801 mL | |
| 5 mM | 0.5676 mL | 2.8380 mL | 5.6760 mL | |
| 10 mM | 0.2838 mL | 1.4190 mL | 2.8380 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.
 Chemical evolution of a series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones17that provided the first mGlu5PAM clinical candidate.ACS Med Chem Lett.2015 May 20;6(6):716-20. |
|---|
 Molecular pharmacological profile of17a. (A) Enhanced calcium release induced by suboptimal concentrations of glutamate (EC20), the PAM CRC, with an EC50for potentiation of 260 nM. (B) Analogue17ainduces a 10-fold leftward shift of the glutamate CRC. (C) Binding study with [3H]-mPEPy, confirming an MPEP sight PAM (Human IC50= 4.37 μM, 82%). (D) mGlu selectivity data (fold-shift at 10 μM) showing that17ais highly selective for mGlu5. Each data point represents the mean ± SD (n= 3). |
 Analogue17ahas antipsychotic-like activity in rats and dose-dependently (3–56.6 mg/kg, po) reverses AHL.#,*,∧p< 0.05 vs VAMP group, Dunnett’s test.ACS Med Chem Lett.2015 May 20;6(6):716-20. |
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