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MedKoo Cat#: 555413 | Name: VU6012962
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

VU6012962 is an orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5x above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.

Chemical Structure

VU6012962
VU6012962
CAS#2313526-86-0

Theoretical Analysis

MedKoo Cat#: 555413

Name: VU6012962

CAS#: 2313526-86-0

Chemical Formula: C21H19F3N4O4

Exact Mass: 448.1358

Molecular Weight: 448.40

Elemental Analysis: C, 56.25; H, 4.27; F, 12.71; N, 12.50; O, 14.27

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 160.00 Ready to ship
25mg USD 350.00 Ready to ship
50mg USD 550.00 Ready to ship
100mg USD 850.00 Ready to ship
200mg USD 1,450.00 Ready to ship
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Related CAS #
No Data
Synonym
VU6012962; VU-6012962; VU 6012962;
IUPAC/Chemical Name
N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide
InChi Key
IQNLJJLZIVCGFI-UHFFFAOYSA-N
InChi Code
InChI=1S/C21H19F3N4O4/c1-30-19-8-14(4-7-18(19)31-10-13-2-3-13)20(29)27-16-9-15(32-21(22,23)24)5-6-17(16)28-12-25-11-26-28/h4-9,11-13H,2-3,10H2,1H3,(H,27,29)
SMILES Code
O=C(NC1=CC(OC(F)(F)F)=CC=C1N2N=CN=C2)C3=CC=C(OCC4CC4)C(OC)=C3
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
Shelf Life
>3 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
More Info
Biological target:
VU6012962 is an orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 negative allosteric modulator (mGlu7 NAM) with an IC50 of 347 nM.
In vitro activity:
As many mGlu allosteric ligands engage induced-fit pockets, SAR can be challenging, and the “right” fit may only be “found” by exploring libraries of analogs via an exercise in strategic serendipity. VU6012962 (7d) proved optimal (IC50 = 350 nM, pIC50 = 6.46 ± 0.10, 12.6 ± 1.5% L-AP4 min) and the most potent within this chemotype to date. Beyond an enhancement in mGlu7 NAM potency, 7d also showed a significant improvement in predicted hepatic clearance (rat CLhep = 15.9 mL min–1 kg–1), generating enthusiasm for the further profiling of 7d. 7d was selective for mGlu7 versus the other seven mGlu receptors (>10 μM versus mGlu1–6,8) and largely devoid of ancillary pharmacology (compound activity at only one target, 5-HT2B receptor, that was greater than 50% at 10 μM) in a Eurofins lead profiling panel of 68 GPCRs, ion channels, and transporters. A 30 mg/kg (ip) tissue distribution study in rat was performed to assess levels of 7d in plasma, brain, and CSF. Here, it was noted that a brain:plasma Kp of 1.24 (([plasma]tot = 598 nM), [brain]tot = 745 nM) and a Kp,uu of 0.38 ([plasma]Unbound = 16.7 nM, [brain]unbound = 6.4 nM); however, the CSF:plasma Kp was 2.15, with levels of 7d in CSF of 1.3 μM, or ~3.8-fold above the in vitro IC50. Reference: J Med Chem. 2019 Feb 14;62(3):1690-1695. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30608678/
In vivo activity:
Having established a 3 mg/kg MED in the EZM assay, 7d was evaluated in two other mouse anxiety models: the light/dark box and marble burying assay. The effects of 3 mg/kg 7d were compared to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX, Figure 4).22 Results from the light/dark box assay showed that administration of either 7d (3 mg/kg ip) or fluoxetine (15 mg/kg ip) increased total time spent in the light side of the chamber compare to vehicle (VEH) controls (Figure 4A). Similarly, both 7d and fluoxetine decreased the number of marbles buried in a mouse marble-burying assay, consistent with an anxiolytic effect, compared to vehicle-control conditions (Figure 4B). The observation of efficacy at the 3 mg/kg dose prompted us to perform a pharmacokinetic assessment at this dose and the 1 h time point used for treatment in mice. These studies revealed values of [plasma]tot = 303 nM and [CSF] = 883 nM; this CSF level is 2.5× higher than the in vitro IC50 of 350 nM. Taken together, mGlu7 NAM 7d decreases anxiety responses in three distinct preclinical models and displays a low of MED of 3 mg/kg, highlighting improvements of this tool compound in the realms of potency, physiochemical properties, disposition, and unbound CSF/brain levels. Reference: J Med Chem. 2019 Feb 14;62(3):1690-1695. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30608678/
Solvent mg/mL mM
Solubility
DMSO 125.0 278.77
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 448.40 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:
In vitro protocol:
1. Reed CW, Yohn SE, Washecheck JP, Roenfanz HF, Quitalig MC, Luscombe VB, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW. Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). J Med Chem. 2019 Feb 14;62(3):1690-1695. doi: 10.1021/acs.jmedchem.8b01810. Epub 2019 Jan 17. PMID: 30608678; PMCID: PMC6501583.
In vivo protocol:
1. Reed CW, Yohn SE, Washecheck JP, Roenfanz HF, Quitalig MC, Luscombe VB, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW. Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). J Med Chem. 2019 Feb 14;62(3):1690-1695. doi: 10.1021/acs.jmedchem.8b01810. Epub 2019 Jan 17. PMID: 30608678; PMCID: PMC6501583.
Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962) Carson W. Reed, Samantha E. Yohn, Jordan P. Washecheck, Hanna F. Roenfanz, Marc C. Quitalig, Vincent B. Luscombe, Matthew T. Jenkins, Alice L. Rodriguez, Darren W. Engers, Anna L. Blobaum, P. Jeffrey Conn, Colleen M. Niswender, and Craig W. Lindsley Publication Date (Web): January 4, 2019 (Brief Article) DOI: 10.1021/acs.jmedchem.8b01810