VU6053371
VU6053371 (BI03738809) is a first-in-class (FIC), selective, orally active, and brain-penetrant metabotropic glutamate receptor subtype 3 (mGlu3) positive allosteric modulator (PAM) with EC50s of 103 nM and 112 nM for human and rat mGlu3. VU6053371 exhibits selectivity for mGlu3 over other mGlu receptor subtypes. VU6053371 exhibits pro-cognitive effects in mouse models. VU6053371 can be used in research schizophrenia, Alzheimer’ s disease and other forms of dementia and cognitive impairment.
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- 화학식: C19H19FN4O2S
- 분자량:386.44
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보관:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
- 순도&문서
- References
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Help & FAQs
Biological Activity
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mGluR3 103 nM (EC50, human) |
mGluR3 112 nM (EC50, rat) |
VU6053371 (compound 13I) is an equipotent mGlu3 PAM for both human (EC50 = 113 nM, 61% Glu Max) and rat (EC50 = 112 nM, 58% Glu Max) and, importantly, inactive (EC50 > 30 μM) for both human and rat mGlu2[1].
VU6053371 is metabolized in mouse, rat, minipig, dog, monkey, and human hepatocytes, with the oxidation product M402A being the most abundant metabolite, whereas the glutathione conjugate M562 is not represented in any species tested[1].
VU6053371 displays a good CYP450 profile (IC50s: 3A4 (>30 μM), 2D6 (>30 μM), 2C9 (16 μM), 1A2 (26 μM)), even against 1A2[1].
VU6053371 shows no time-dependent CYP450 inhibition at 3A4, is negative in the mini-AMES (with and without S9), and exhibits no CV/QT concern in a functional EP hERG assay (IC50 > 30 μM)[1].
VU6053371 (10 μM 1 h) leeds to the identification of a GSH conjugate (M691) and forms 5.9% of this adduct after incubation in fortified microsomes with human liver cytosol and GSH[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
VU6053371 (1-10 mg/kg; p.o.) affords a robust PK/PD relationship for efficacy in the NOR paradigm when unbound brain exposures are at or above the rat mGlu3 PAM EC50[1].
VU6053371 (100-300mg/kg; p.o.; twice a day; 9 days) exhibits an unfavorable toxicological profile in rats[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male rats[1].
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Dosage:30 mg/kg, 100 mg/kg, 300 mg/kg
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Administration:p.o.; twice a day; 9 days
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Result:Demonstrated systemic drug exposure in all animals treated with VU6053371.
Developed significant clinical symptoms accompanied by a decrease in body temperature at a dose of 100-300 mg/kg.
Showed mildly to moderately reduced reticulocyte counts on day 8 at a dose of 30-300 mg/kg.
Had moderately lower white blood cell, lymphocyte, and monocyte counts at a single dose of 300 mg/kg compared to controls.
Showed diffuse bone marrow hypocellularity at 100 mg/kg/dose.
Exhibited mild multifocal inflammatory foci in the myocardium, not limited to a specific heart region at all high-dose males.
Showed diffuse bone marrow hypocellularity at 100 mg/kg/dose.
Exhibited mild multifocal inflammatory foci in the myocardium, with myocardial fiber injury confined to areas of inflammatory infiltration,and no fibrosis or no abnormal cardiac Troponin/cleaved Caspase-3 IHC signals at high-dose.
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Animal Model:Male Sprague-Dawley rats subjected to habituation training in NOR arenas[1].
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Dosage:1 mg/kg, 3 mg/kg, 10 mg/kg
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Administration:p.o.;single dose
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Result:Dose-dependently enhanced recognition memory in rats with a minimum effective dose (MED) of 3 mg/kg PO and a near maximum response at 10 mg/kg PO.
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Animal Model:Male Sprague-Dawley rats (PO 0.5% natrosol/0.015% Tween 80 in water, 30 min) [1].
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Dosage:1 mg/kg, 3 mg/kg, 10 mg/kg
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Administration:p.o.;single dose
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Result:Achieved unbound brain levels of 151 nM (~1.35-fold the rat mGlu3 PAM EC50) at the 3 mg/kg PO MED, and produced maximal efficacy at 10 mg/kg PO (free brain = 385 nM, ~3.43-fold the EC50.
Chemical Information
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분자량 386.44
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화학식 C19H19FN4O2S
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SMILES
FC1=CC(C2=C(C)SC(NC3=CN=C(C(C)(C)O)N=C3)=C2C(N)=O)=CC=C1
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Synonyms
BI03738809
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Please store the product under the recommended conditions in the Certificate of Analysis.
순도&문서
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
VU6053371 Related Classifications
HY-184475 Related Classifications
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