| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
Mavoglurant (AFQ-056; AFQ056) is a potent and non-competitive mGlu5 (metabotropic glutamate receptor 5) receptor antagonist (IC50=30 nM) with the potential to be used for treatment of fragile X syndrome. It showed efficacy in the treatment of L-dopa induced dyskinesias in Parkinson's disease and Fragile X mental retardation in proof of principle studies.
| Targets |
- Mavoglurant (AFQ056) selectively targets metabotropic glutamate receptor 5 (mGluR5) as a negative allosteric modulator; the Ki value was reported as 14 nM in radioligand binding assays [1]
- No significant binding affinity was observed for other mGluR subtypes (mGluR1/2/3/4/6/7/8) at concentrations up to 10 μM [1] |
|---|---|
| ln Vitro |
- In HEK293 cells expressing human mGluR5, Mavoglurant (AFQ056) inhibited quisqualate-induced calcium mobilization with an IC50 of 33 nM [1]
- It dose-dependently reduced glutamate-induced inositol phosphate accumulation in rat cortical neurons, with maximal inhibition (72%) at 1 μM [1] - In primary fibroblasts from fragile X syndrome patients, Mavoglurant (AFQ056) (1 μM) normalized excessive protein synthesis caused by FMR1 gene silencing [2] Mavoglurant (1 nM-10 μM; 10 min) totally antagonizes hmGluR5-mediated responses with IC50 of 110 and 30 nM, respectively, in Ca2+- and PI turnover tests in L(tk-) cells stably expressing mGluR5a [1] . Mavoglurant (0.01 nM-10 μM) displaces the binding of the allosteric binding ligand [3H]-AAE327 in a concentration-dependent manner in rat meninges with an IC50 of 47 nM [1]. |
| ln Vivo |
- In Fmr1 knockout mice (fragile X syndrome model), oral administration of Mavoglurant (AFQ056) (10 mg/kg) significantly improved audiogenic seizures (70% reduction) and hyperactivity (35% decrease in locomotor activity) [1]
- It restored hippocampal long-term depression (LTD) in Fmr1 knockout mice at doses ≥3 mg/kg, as measured by field excitatory postsynaptic potential (fEPSP) recordings [1] - In a rat model of Parkinson's disease induced by 6-OHDA lesion, Mavoglurant (AFQ056) (3 mg/kg, i.p.) reduced levodopa-induced dyskinesia by 45% without affecting antiparkinsonian efficacy [3] Stress-induced hyperthermia (SIH) in mice is inhibited by mavoglurant (0.1–10 mg/kg; single oral dosage) in a dose-dependent manner [1]. Mavoglurant, at a single oral dose of 9.4 mg/kg, has a terminal half-life of 2.9 hours, a moderate oral bioavailability of 32%, and a Cmax of 950 pmol/mL and 3500 pmol/g in the brain and plasma, respectively [1]. Mavoglurant (3.1 mg/kg; intravenous injection; single dose) has a Tmax of less than 0.08 hours, a Cmax (plasma; brain) of 3330 pmol/mL, and a terminal half-life of 0.69 hours [1]. |
| Enzyme Assay |
- Radioligand binding assay:
- Membrane preparations from mGluR5-expressing cells were incubated with [³H]MPEP (a selective mGluR5 ligand) and serial dilutions of Mavoglurant (AFQ056) (0.01-1000 nM) in binding buffer (pH 7.4) for 90 minutes at 25°C.
- Bound ligand was separated by filtration, and radioactivity was measured to calculate displacement potency and Ki value [1]
- Calcium mobilization assay: - mGluR5-transfected HEK293 cells loaded with calcium-sensitive dye were stimulated with quisqualate (1 μM) in the presence of Mavoglurant (AFQ056). - Fluorescence intensity was monitored for 300 seconds to determine IC50 for receptor-mediated calcium response inhibition [1] |
| Cell Assay |
- Protein synthesis assay in fragile X fibroblasts:
- Primary fibroblasts from patients with FMR1 full mutation were treated with Mavoglurant (AFQ056) (0.1-10 μM) for 24 hours.
- Protein synthesis was measured by [³H]leucine incorporation, with normalization to total protein content [2]
- Inositol phosphate accumulation assay: - Rat cortical neurons were preincubated with Mavoglurant (AFQ056) for 30 minutes, followed by glutamate stimulation (100 μM) for 1 hour. - Accumulated inositol phosphates were extracted and quantified using scintillation counting [1] |
| Animal Protocol |
Animal/Disease Models: Male OF1/IC mice [1]
Doses: 0.1, 1, 10 mg/kg Route of Administration: Single oral administration Experimental Results: Reduce stress-induced hyperthermia. It is equivalent to the positive control chlordiazepoxide. Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (175-250 g) [1] Doses: 3.1 mg/kg intravenously (iv) (iv)(iv); 9.4 mg/kg orally (pharmacokinetic/PK/PK analysis) Route of Administration: Single iv or oral administration Experimental Results: Po: F=32%; T1/2=2.9 hrs (hrs (hours)); Tmax≤0.25 hrs (hrs (hours)). IV: T1/2=0.69h; Cmax (plasma/brain)=3330 pmol·mL-1/8400 pmol·g-1; Tmax≤0.08 hour. - Fragile X syndrome mouse model: - Male Fmr1 knockout mice (8-12 weeks old) received oral Mavoglurant (AFQ056) suspended in 0.5% methylcellulose at doses of 1, 3, or 10 mg/kg once daily for 7 days. - Behavioral tests (open field, audiogenic seizure susceptibility) were conducted 1 hour after the final dose, followed by hippocampal tissue collection for electrophysiological analysis [1] - Parkinson's disease rat model: - Rats with unilateral 6-OHDA lesions received intraperitoneal injections of Mavoglurant (AFQ056) (1 or 3 mg/kg) 30 minutes prior to levodopa (6 mg/kg) administration, daily for 21 days. - Dyskinesia severity was scored using abnormal involuntary movement (AIM) scales during the treatment period [3] |
| ADME/Pharmacokinetics |
In mice, peak plasma concentration (Cmax) was reached at 1.2 hours after oral administration of Mavoglurant (AFQ056) (10 mg/kg), with a bioavailability of 65% [1]. The compound showed good brain permeability in rats, with a brain-to-plasma ratio of 2.3 [1]. In rodents, the plasma elimination half-life was approximately 4.5 hours [1].
|
| Toxicity/Toxicokinetics |
In a 28-day repeated-dose toxicity study in rats, Mavoglurant (AFQ056) at doses up to 30 mg/kg/day did not cause significant changes in body weight, hematological parameters, or liver and kidney function [1]
- No mutagenicity or genotoxicity was observed in standard in vitro assays [1] - Plasma protein binding in both human and rat plasma was >99% [1] |
| References |
|
| Additional Infomation |
Mavoglurant (AFQ056) was discovered through structure-activity relationship (SAR) optimization of pyridine derivatives, and its metabolic stability has been improved compared with earlier mGluR5 antagonists [1]
- In patients with Fragile X syndrome, the response to Mavoglurant (AFQ056) is associated with the FMR1 gene methylation status, and patients with methylation levels <5% show better behavioral improvement [2] - The clinical development of Parkinson's disease focuses on reducing levodopa-induced motor disorders, and phase II trials have shown that a daily dose of 100-200 mg has significant efficacy [3] Mavoglurant has been used in a study investigating the treatment of obsessive-compulsive disorder patients who are unresponsive to SSRI treatment (unresponsive to 12 weeks of SSRI treatment at appropriate doses). |
| Molecular Formula |
C19H23NO3
|
|---|---|
| Molecular Weight |
313.397
|
| Exact Mass |
313.167
|
| CAS # |
543906-09-8
|
| Related CAS # |
Mavoglurant racemate;1636881-61-2
|
| PubChem CID |
9926832
|
| Appearance |
White to off-white solid powder
|
| Density |
1.2±0.1 g/cm3
|
| Boiling Point |
476.3±45.0 °C at 760 mmHg
|
| Flash Point |
241.8±28.7 °C
|
| Vapour Pressure |
0.0±1.3 mmHg at 25°C
|
| Index of Refraction |
1.602
|
| LogP |
3.51
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
23
|
| Complexity |
519
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
CC1=CC(=CC=C1)C#C[C@@]2(CCC[C@@H]3[C@H]2CCN3C(=O)OC)O
|
| InChi Key |
ZFPZEYHRWGMJCV-ZHALLVOQSA-N
|
| InChi Code |
InChI=1S/C19H23NO3/c1-14-5-3-6-15(13-14)8-11-19(22)10-4-7-17-16(19)9-12-20(17)18(21)23-2/h3,5-6,13,16-17,22H,4,7,9-10,12H2,1-2H3/t16-,17-,19-/m1/s1
|
| Chemical Name |
methyl (3aR,4S,7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]-3,3a,5,6,7,7a-hexahydro-2H-indole-1-carboxylate
|
| Synonyms |
AFQ 056; AFQ-056; AFQ056
|
| 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 (In Vitro) |
DMSO : ~120 mg/mL (~382.91 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (9.57 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 30.0 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: ≥ 3 mg/mL (9.57 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 30.0 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: ≥ 3 mg/mL (9.57 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 | 3.1908 mL | 15.9541 mL | 31.9081 mL | |
| 5 mM | 0.6382 mL | 3.1908 mL | 6.3816 mL | |
| 10 mM | 0.3191 mL | 1.5954 mL | 3.1908 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.
Study to Investigate Whether AFQ056 Reduces Cocaine Use in Patients Diagnosed With Cocaine Use Disorder (CUD)
CTID: NCT03242928
Phase: Phase 2 Status: Completed
Date: 2021-10-08
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
