| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 100mg |
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| Targets |
Valiglurax selectively targets the metabotropic glutamate receptor subtype 4 (mGlu4), acting as a positive allosteric modulator (PAM). It binds to an allosteric site on the receptor, distinct from the orthosteric glutamate binding site, and enhances the receptor's response to its endogenous agonist, glutamate. This potentiation of mGlu4 signaling leads to a decrease in neurotransmitter release at synapses within the basal ganglia, specifically reducing the output of the indirect pathway, which is overactive in Parkinson's disease. The high selectivity of Valiglurax for mGlu4 over other receptor subtypes is crucial for minimizing off-target effects and achieving a clean pharmacological profile.
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| ln Vitro |
In vitro, Valiglurax demonstrates potent activity as an mGlu4 PAM. In calcium mobilization assays using human mGlu4/Gqi5 cells, it exhibits an EC50 of 64.6 nM. In rat mGlu4 GIRK (G protein-coupled inwardly rectifying potassium channel) assays, it shows an EC50 of 197 nM. These data confirm its high potency in modulating mGlu4 receptor function across species. Furthermore, it displays excellent selectivity for mGlu4 over other mGlu receptor subtypes, as well as other CNS targets, ensuring that its pharmacological effects are mediated specifically through mGlu4 potentiation.
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| ln Vivo |
In vivo, Valiglurax has been evaluated in preclinical models of Parkinson's disease, where it demonstrates robust efficacy. Its oral bioavailability and excellent CNS penetration allow for significant brain exposure following systemic administration, which is essential for a CNS-targeted therapeutic. In rodent models, it has been shown to effectively reduce or eliminate motor symptoms, such as those seen in the haloperidol-induced catalepsy model or the 6-OHDA lesion model, which are standard tests for anti-parkinsonian activity. These effects are attributed to its ability to potentiate mGlu4 signaling within the basal ganglia circuitry. Its overall in vivo profile, coupled with favorable pharmacokinetics, supports its evaluation as a preclinical development candidate.
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| Enzyme Assay |
The in vitro enzyme/receptor binding (non-cell) assay for Valiglurax typically involves the use of membrane preparations from cells expressing recombinant human or rat mGlu4 receptors. These membranes are incubated with a radiolabeled ligand that binds to the mGlu4 receptor, alongside varying concentrations of Valiglurax. The binding affinity (Ki) and allosteric modulation are then determined by assessing the displacement of the radiolabeled ligand or by measuring the potentiation of a sub-maximal concentration of glutamate in a functional assay. For example, [³H]-LY341495, a known mGlu receptor antagonist, can be used as the radioligand. The potency of Valiglurax in enhancing glutamate-induced GIRK channel activity is a key readout for its PAM activity.
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| Cell Assay |
In vitro cell-based assays for Valiglurax are performed using cell lines that stably express human or rat mGlu4 receptors, often engineered to co-express a promiscuous G protein (Gqi5) to couple the receptor to the calcium mobilization pathway. Typically, HEK293 cells are seeded in multi-well plates and loaded with a calcium-sensitive fluorescent dye. The cells are then treated with varying concentrations of Valiglurax, followed by a sub-maximal concentration of glutamate. The increase in intracellular calcium is measured using a fluorescence plate reader, and the EC50 value is calculated from the dose-response curve. Alternatively, cells expressing mGlu4 and GIRK channels can be used, where the PAM activity is assessed by measuring the potentiation of GIRK-mediated thallium flux.
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| Animal Protocol |
Animal/Disease Models: Haloperidol-induced catalepsy (HIC) in rats [1]. Valiglurax (VU0652957; 0.3-30 mg/kg; po) restores haloperidol-induced catalepsy (HIC) in a dose-resetting manner )[1]. 0.3-30 mg/kg
Route of Administration: Oral Experimental Results: Reverse haloperidol-induced catalepsy (HIC) in rats in a dose-dependent manner. In vivo animal experiments for Valiglurax are conducted in rodent models of Parkinson's disease, such as the haloperidol-induced catalepsy model, the 6-hydroxydopamine (6-OHDA) lesioned rat model, or the reserpine-induced akinesia model. In these studies, Valiglurax is typically administered orally to evaluate its efficacy in reversing motor deficits. Behavioral assessments include measurements of catalepsy (bar test), locomotor activity, and forelimb use asymmetry. Additionally, pharmacokinetic-pharmacodynamic (PK-PD) studies are performed to correlate plasma and brain concentrations of Valiglurax with its pharmacological effect, confirming its CNS penetration and target engagement. |
| ADME/Pharmacokinetics |
Valiglurax exhibits attractive DMPK properties across species, including high oral bioavailability and excellent CNS penetration. It is rapidly absorbed following oral administration, with measurable concentrations in both plasma and brain tissue. Its half-life and clearance are consistent with once or twice daily dosing in preclinical species. To support IND-enabling toxicology studies, a spray-dried dispersion (SDD) formulation was developed to enhance its solubility and bioavailability. Detailed pharmacokinetic parameters, such as Cmax, Tmax, and AUC, have been characterized and are favorable for a CNS drug candidate.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies have been conducted to evaluate the safety profile of Valiglurax in support of its advancement as a development candidate. IND-enabling toxicology studies were performed using the SDD formulation. In these studies, Valiglurax demonstrated a favorable safety profile at doses that are efficacious in animal models of Parkinson's disease. No significant off-target toxicity or adverse effects on major organ systems were observed, supporting its potential for further clinical development.
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| References | |
| Additional Infomation |
mGlu4 positive allosteric modifier
Valiglurax is a research compound that has been evaluated as a preclinical development candidate for Parkinson's disease. It represents a promising non-dopaminergic approach to treating PD, with a potential for disease modification in addition to symptomatic relief. Its discovery and development highlight the challenges and successes in optimizing allosteric modulators for CNS targets. It has not yet been approved for clinical use and remains an investigational agent for research purposes. |
| Molecular Formula |
C16H10F3N5
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|---|---|
| Molecular Weight |
329.279312610626
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| Exact Mass |
329.088
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| CAS # |
1976050-09-5
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| Related CAS # |
1976050-09-5;
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| PubChem CID |
134191471
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
446
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1C2C=CC(=CC=2C=CN=1)NC1=C2C=CC=NC2=NN1)(F)F
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| InChi Key |
RUEXKBWCUUFJMY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H10F3N5/c17-16(18,19)13-11-4-3-10(8-9(11)5-7-20-13)22-15-12-2-1-6-21-14(12)23-24-15/h1-8H,(H2,21,22,23,24)
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| Chemical Name |
N-(2H-pyrazolo[3,4-b]pyridin-3-yl)-1-(trifluoromethyl)isoquinolin-6-amine
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~83.33 mg/mL (~253.07 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0369 mL | 15.1846 mL | 30.3693 mL | |
| 5 mM | 0.6074 mL | 3.0369 mL | 6.0739 mL | |
| 10 mM | 0.3037 mL | 1.5185 mL | 3.0369 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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