CHDI-340246
CHDI-340246 is an orally active kynurenine monooxygenase (KMO) inhibitor. CHDI-340246 blocks KMO activity, alters the metabolic flux of the kynurenine pathway, inhibits the production of 3-hydroxykynurenine and quinolinic acid, elevates the levels of kynurenine and kynurenic acid, and restores electrophysiological abnormalities in transgenic mouse models of Huntington's disease. CHDI-340246 can be used in studies related to Huntington's disease.
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- CAS. Nr.: 1426319-74-5
- Formel: C14H11ClN2O3
- Molecular Weight:290.70
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Help & FAQs
Biologische Aktivität
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO | IC50 |
0.008 μM
Compound: 75
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Inhibition of human KMO transfected in CHO cells assessed as conversion of kynurenine to 3-hydroxykynurenine by LC-MS/MS analysis
Inhibition of human KMO transfected in CHO cells assessed as conversion of kynurenine to 3-hydroxykynurenine by LC-MS/MS analysis
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[PMID: 25590515] |
CHDI-340246 potently inhibits kynurenine-3-monooxygenase (KMO) in rodent liver, with an IC50 of 0.5 nM[2].
CHDI-340246 inhibits cellular KMO activity, with an IC50 of 63.81 nM in primary rat microglia, 89.73 nM in human peripheral blood mononuclear cells (PBMCs), and 20-80 nM in CHO cells overexpressing mouse, human or rat KMO[2].
CHDI-340246 (administered 20 minutes before recording at a concentration of 1 μM and maintained throughout until the end of LTP recording) acutely rescues hippocampal CA3:CA1 LTP deficits in brain slices from 8-week-old R6/2 mice, without affecting basal glutamatergic transmission in brain slices from either R6/2 or wild-type mice[2].
CHDI-340246 (100 nM; 15-30 min) acutely restores abnormal membrane excitability (inducing membrane hyperpolarization and reducing membrane resistance) of striatal SPNs in 7- to 8-week-old R6/2 mice[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Tmax | Cmax | AUC0-t | T1/2 | CL | Vdss | F | Tmax (Plasma) | T1/2 (Plasma) | Tmax (Brain) | Cmax (Brain) | T1/2 (Brain) |
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| Mice[1] | 5 mg/kg | i.v. | / | / | 43 μM·h | / | 0.40 L/h/kg | 0.44 L/kg | / | 0.083 h | 1.40 h | 0.083 h | 0.94 μM | 0.84 h |
| Mice[1] | 10 mg/kg | p.o. | / | 67 μM | 73 μM·h | / | / | / | 60 % | 0.25 h | 3.2 h | 0.50 h | 0.81 μM | 1.1 h |
| Rat[1] | 5 mg/kg | i.v. | / | / | 73 μM·h | / | 0.29 L/h/kg | 0.32 L/kg | / | 0.083 h | 1.8 h | 0.083 h | 1.60 μM | 0.7 h |
| Rat[1] | 10 mg/kg | p.o. | / | 23 μM | 91 μM·h | / | / | / | 64 % | 1.0 h | 2.4 h | 1.0 h | 0.42 μM | 1.7 h |
| Dog[1] | 2.5 mg/kg | i.v. | 0.083 h | 49.7 μM | 88 μM·h | 1.8 h | 0.11 L/h/kg | 0.23 L/kg | / | / | / | / | / | / |
| Dog[1] | 5.0 mg/kg | p.o. | 0.67 h | 22 μM | 120 μM·h | 3.6 h | / | / | 68 % | / | / | / | / | / |
| Cynomolgus Monkey[1] | 3 mg/kg | i.v. | 0.083 h | 104 μM | 220 μM·h | 9.41 h | 0.045 L/h/kg | 0.31 L/kg | / | / | / | / | / | / |
| Cynomolgus Monkey[1] | 3 mg/kg | p.o. | 3.38 h | 188 μM | 166 μM·h | 4.82 h | / | / | 75 % | / | / | / | / | / |
CHDI-340246 (30 mg/kg; p.o.; single administration; pre-administered 30 min prior to Kyn treatment) inhibits central KMO activity in wild-type mice and significantly attenuates the Kyn-induced increases in extracellular 3-OH-Kyn and Quin levels in the striatum[2].
CHDI-340246 (0-100 mg/kg; p.o.; twice daily; for 4-8 weeks) improves survival rate in male mice, partially ameliorates striatal glutamatergic input deficits (measured by mEPSC frequency), but fails to sustainably improve behavioral deficits or brain volume loss, and only partially normalizes striatal creatine levels in R6/2 Huntington's disease model mice at the highest dose[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Q175 heterozygous, wild-type (male)[2]
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Dosage:30 mg/kg; 60 mg/kg; 100 mg/kg
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Administration:p.o.; single dose
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Result:Reached striatal Cmax of Kyn 75-280 nM, KynA 15-30 nM, and AA 15-30 nM in Q175 heterozygous mice.
Reached 3-OH-Kyn Cmax 1.6-2 nM from a baseline of 0.8 nM in Q175 heterozygous mice.
Showed higher AUC values for Kyn and KynA at 60 and 100 mg/kg than at 30 mg/kg in Q175 heterozygous mice, driven by longer exposure.
Showed saturation of Cmax values for Kyn and KynA at doses above 30 mg/kg in Q175 heterozygous mice.
Had higher Kyn AUC values in wild-type mice than Q175 heterozygous mice at all doses tested.
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Animal Model:wild-type[2]
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Dosage:30 mg/kg
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Administration:p.o.; single dose; pre-administered 30 minutes prior to Kyn
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Result:Reduced the Kyn-induced elevation of brain extracellular 3-OH-Kyn levels by 75-90%.
Reduced the Kyn-induced elevation of brain extracellular Quin levels by 60-80%.
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Animal Model:R6/2 transgenic, wild-type littermates (equal gender split, 4 weeks old)[2]
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Dosage:10 mg/kg; 30 mg/kg; 60 mg/kg; 100 mg/kg
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Administration:p.o.; twice daily; 8 weeks
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Result:Did not produce consistent effects on locomotor function, grip strength, rotarod performance, or open field activity in R6/2 mice.
Improved median survival rates in male R6/2 mice treated with 60 or 100 mg/kg compared to vehicle-treated male R6/2 mice.
Showed no significant effects on whole brain, striatal, or cortical volume via MRI.
Normalized striatal creatine levels towards wild-type levels at the 100 mg/kg dose via MRS.
Chemical Information
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CAS. Nr. 1426319-74-5
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Molecular Weight 290.70
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Formel C14H11ClN2O3
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SMILES
O=C(C1=NC=NC(C2=CC(Cl)=C(OC3CC3)C=C2)=C1)O
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Khetarpal V, et al. Pharmacokinetics and metabolic disposition of a potent and selective kynurenine monooxygenase inhibitor, CHDI-340246, in laboratory animals. Xenobiotica. 2021;51(10):1155-1180. [Content Brief]
[2]. Beaumont V, et al. The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease. Exp Neurol. 2016;282:99-118. [Content Brief]
[3]. Toledo-Sherman LM, et al. Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease. J Med Chem. 2015;58(3):1159-1183. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
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