JNJ-46778212

Alias: JNJ-46778212; JNJ 46778212; JNJ46778212; VU0409551; VU-0409551; VU 0409551
Cat No.:V4511 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 anEC50of 260 nM.
JNJ-46778212 Chemical Structure CAS No.: 1363281-27-9
Product category: mGluR
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
Targets
mGlu5 Receptor ( EC50 = 260 nM )
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].
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].
References

[1]. Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia. ACS Med Chem Lett. 2015 May 20;6(6):716-20.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C20H17FN2O3
Molecular Weight
352.358988523483
Exact Mass
352.12
Elemental Analysis
C, 68.17; H, 4.86; F, 5.39; N, 7.95; O, 13.62
CAS #
1363281-27-9
Appearance
Solid powder
SMILES
C1CN(CC2=C1N=C(O2)COC3=CC=CC=C3)C(=O)C4=CC=C(C=C4)F
InChi Key
QUZLMKNNIUSREV-UHFFFAOYSA-N
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
Chemical Name
(4-fluorophenyl)-[2-(phenoxymethyl)-6,7-dihydro-4H-[1,3]oxazolo[5,4-c]pyridin-5-yl]methanone
Synonyms
JNJ-46778212; JNJ 46778212; JNJ46778212; VU0409551; VU-0409551; VU 0409551
HS Tariff Code
2934.99.9001
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~100 mg/mL (~283.8 mM)
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.

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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.

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Biological Data
  • JNJ-46778212


    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.2015 May 20;6(6):716-20.

  • JNJ-46778212


    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).

  • JNJ-46778212


    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.2015 May 20;6(6):716-20.

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