Mavoglurant
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MedKoo CAT#: 319677

CAS#: 543906-09-8

Description: Mavoglurant, aslo known as AFQ056, is an experimental drug candidate for the treatment of fragile X syndrome. Mavoglurant exerts its effect as an antagonist of the metabotropic glutamate receptor 5 (mGLU5). Novartis discontinued development of mavoglurant for fragile X syndrome in April 2014 following disappointing trial results. Currently Novartis is conducting a clinical trial with this drug on obsessive compulsive disorder.


Chemical Structure

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Mavoglurant
CAS# 543906-09-8

Theoretical Analysis

MedKoo Cat#: 319677
Name: Mavoglurant
CAS#: 543906-09-8
Chemical Formula: C19H23NO3
Exact Mass: 313.1678
Molecular Weight: 313.397
Elemental Analysis: C, 72.82; H, 7.40; N, 4.47; O, 15.32

Price and Availability

Size Price Availability Quantity
1.0mg USD 190.0 Same day
5.0mg USD 550.0 Same day
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Synonym: AFQ056; AFQ-056; AFQ 056; Mavoglurant.

IUPAC/Chemical Name: methyl (3aR,4S,7aR)-4-hydroxy-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate

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

SMILES Code: O=C(N1CC[C@@]2([H])[C@@](C#CC3=CC=CC(C)=C3)(O)CCC[C@@]12[H])OC

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Mavoglurant (AFQ056) is a potent, selective, non-competitive and orally active mGluR5 antagonist, with an IC50 of 30 nM.
In vitro activity: To determine whether AFQ056 may have secondary effects on the methylation and transcription of FMR1, three FXS lymphoblastoid cell lines and one normal control male line were treated. A quantitative RT-PCR was performed to assess transcriptional reactivation of the FMR1 gene. No FMR1-mRNA increase was observed after treatment with AFQ056 in any of the four cell lines, with respect to the untreated controls. The partial decrease in FMR1 transcription observed in WT at 1 mM AFQ056 after 3 and 8 days of treatment (panel A) was due at least in part to cell mortality. AFQ056 treatment had no effect on methylation, leaving the promoter as methylated as in the untreated controls both WT and FXS (Figure 22). These results demonstrate that the AFQ056 effect on fully methylated FXS patients is not due to a secondary effect on DNA methylation and consequent transcriptional activation of FMR1. Reference: BMC Med Genet. 2012; 13: 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320553/
In vivo activity: In this study, the activity of the metabotropic glutamate receptor-5 (mGluR5) was inhibited using AFQ056/Mavoglurant, a drug that is assumed to normalize excitatory/inhibitory neural signaling imbalances in FXS. Resting-state-fMRI (rs-fMRI) and diffusion-weighted imaging (DWI) were employed to test whether Mavoglurant re-established brain connectivity - at least partly - within some of the affected circuits in Fmr1-/y mice that are related to social behavior deficits. In line with previous findings, it was observed that Fmr1/y mice exhibited impaired social interaction, reduced connectivity in three main functional networks and altered network topology. At the group level, Mavoglurant did neither rescue abnormal social behavioral nor white matter abnormalities; however, for some, but not all of these circuits Mavoglurant had a genotype-specific effect of restoring functional connectivity. Analyses of network connectivity strength showed that chronic treatment with AFQ056/Mavoglurant was sufficient to restore the connectivity profile towards Fmr1+/y levels in temporal associative and somatosensory networks (Genotype × Treatment interaction, p-value = 0.009 and 0.001, respectively), but not in anterior-posterior cingulate network (p-value = 0.136).These results show that rs-fMRI connectivity is sufficiently sensitive to pick up system-level changes after the pharmacological inhibition of mGluR5 activity. Overall, the effects of Mavoglurant are confined to specific networks suggesting that behavioral benefits might be restricted to narrow functional domains. Reference: Neuroimage. 2019 May 1;191:392-402. https://pubmed.ncbi.nlm.nih.gov/30807820/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 120.0 382.91

Preparing Stock Solutions

The following data is based on the product molecular weight 313.397 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Tabolacci E, Pirozzi F, Gomez-Mancilla B, Gasparini F, Neri G. The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro. BMC Med Genet. 2012 Mar 7;13:13. doi: 10.1186/1471-2350-13-13. PMID: 22397687; PMCID: PMC3320553. 2. Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PMID: 25316499. 3. Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PMID: 25316499. 3. Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PMID: 25316499. 3. Zerbi V, Markicevic M, Gasparini F, Schroeter A, Rudin M, Wenderoth N. Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice. Neuroimage. 2019 May 1;191:392-402. doi: 10.1016/j.neuroimage.2019.02.051. Epub 2019 Feb 23. PMID: 30807820.
In vitro protocol: 1. Tabolacci E, Pirozzi F, Gomez-Mancilla B, Gasparini F, Neri G. The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro. BMC Med Genet. 2012 Mar 7;13:13. doi: 10.1186/1471-2350-13-13. PMID: 22397687; PMCID: PMC3320553. 2. Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PMID: 25316499.
In vivo protocol: 1. Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PMID: 25316499. 2. Zerbi V, Markicevic M, Gasparini F, Schroeter A, Rudin M, Wenderoth N. Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice. Neuroimage. 2019 May 1;191:392-402. doi: 10.1016/j.neuroimage.2019.02.051. Epub 2019 Feb 23. PMID: 30807820.

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1: Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, von Raison F. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016 Jan 13;8(321):321ra5. doi: 10.1126/scitranslmed.aab4109. PubMed PMID: 26764156.

2: Wendling T, Dumitras S, Ogungbenro K, Aarons L. Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics. J Pharmacokinet Pharmacodyn. 2015 Dec;42(6):639-57. doi: 10.1007/s10928-015-9430-4. Epub 2015 Aug 1. PubMed PMID: 26231433.

3: Sivasubramanian R, Chakraborty A, Rouzade-Dominguez ML, Neelakantham S, Jakab A, Mensinga T, Legangneux E, Woessner R, Ufer M. Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women. Int J Clin Pharmacol Ther. 2015 Jul;53(7):550-6. doi: 10.5414/CP202321. PubMed PMID: 25943176.

4: Wendling T, Ogungbenro K, Pigeolet E, Dumitras S, Woessner R, Aarons L. Model-based evaluation of the impact of formulation and food intake on the complex oral absorption of mavoglurant in healthy subjects. Pharm Res. 2015 May;32(5):1764-78. doi: 10.1007/s11095-014-1574-1. Epub 2014 Nov 26. PubMed PMID: 25425054.

5: Vranesic I, Ofner S, Flor PJ, Bilbe G, Bouhelal R, Enz A, Desrayaud S, McAllister K, Kuhn R, Gasparini F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033. Epub 2014 Sep 20. PubMed PMID: 25316499.

6: Petrov D, Pedros I, de Lemos ML, Pallàs M, Canudas AM, Lazarowski A, Beas-Zarate C, Auladell C, Folch J, Camins A. Mavoglurant as a treatment for Parkinson's disease. Expert Opin Investig Drugs. 2014 Aug;23(8):1165-79. doi: 10.1517/13543784.2014.931370. Epub 2014 Jun 24. Review. PubMed PMID: 24960254.

7: Gomez-Mancilla B, Berry-Kravis E, Hagerman R, von Raison F, Apostol G, Ufer M, Gasparini F, Jacquemont S. Development of mavoglurant and its potential for the treatment of fragile X syndrome. Expert Opin Investig Drugs. 2014 Jan;23(1):125-34. doi: 10.1517/13543784.2014.857400. Epub 2013 Nov 20. Review. PubMed PMID: 24251408.

8: Kumar R, Hauser RA, Mostillo J, Dronamraju N, Graf A, Merschhemke M, Kenney C. Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson's disease patients. Int J Neurosci. 2016 Jan;126(1):20-4. doi: 10.3109/00207454.2013.841685. Epub 2015 Aug 18. PubMed PMID: 24007304.

9: Walles M, Wolf T, Jin Y, Ritzau M, Leuthold LA, Krauser J, Gschwind HP, Carcache D, Kittelmann M, Ocwieja M, Ufer M, Woessner R, Chakraborty A, Swart P. Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects. Drug Metab Dispos. 2013 Sep;41(9):1626-41. doi: 10.1124/dmd.112.050716. Epub 2013 Jun 17. PubMed PMID: 23775850.

10: Pop AS, Levenga J, de Esch CE, Buijsen RA, Nieuwenhuizen IM, Li T, Isaacs A, Gasparini F, Oostra BA, Willemsen R. Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant. Psychopharmacology (Berl). 2014 Mar;231(6):1227-35. doi: 10.1007/s00213-012-2947-y. Epub 2012 Dec 21. PubMed PMID: 23254376.

11: Gantois I, Pop AS, de Esch CE, Buijsen RA, Pooters T, Gomez-Mancilla B, Gasparini F, Oostra BA, D'Hooge R, Willemsen R. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res. 2013 Feb 15;239:72-9. doi: 10.1016/j.bbr.2012.10.059. Epub 2012 Nov 6. PubMed PMID: 23142366.

12: Jakab A, Winter S, Raccuglia M, Picard F, Dumitras S, Woessner R, Mistry S, Chudasama J, Guttikar S, Kretz O. Validation of an LC-MS/MS method for the quantitative determination of mavoglurant (AFQ056) in human plasma. Anal Bioanal Chem. 2013 Jan;405(1):215-23. doi: 10.1007/s00216-012-6456-y. Epub 2012 Oct 13. PubMed PMID: 23064707.