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.
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 |
| PubChem CID | 56846694 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 3 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 26 |
| Complexity | 478 |
| Defined Atom Stereocenter Count | 0 |
| 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) |
Biological Activity
| 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. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~100 mg/mL (~283.8 mM) |
| 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. 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. 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 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 | 2.8380 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 |