2. Metabolic Enzyme/Protease
  3. KMO
  4. 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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CHDI-340246

CHDI-340246 Chemical Structure

CAS No. : 1426319-74-5

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CHDI-340246 Related Antibodies

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Description

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[1][2][3].

In Vitro

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.

CHDI-340246 Related Antibodies
Parmacokinetics
Species Dose Route Tmax Cmax AUC0-t T1/2 CL Vdss F Tmax (Plasma) T1/2 (Plasma) Tmax (Brain) Cmax (Brain) T1/2 (Brain)
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 % / / / / /
In Vivo

CHDI-340246 (0-100 mg/kg; p.o.; single administration) regulates striatal kynurenine pathway metabolites in Q175 heterozygous Huntington's disease model mice in a dose-dependent manner, and induces a sustained increase in Kyn and KynA at high doses[2].
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.

Animal Model: Q175 heterozygous, wild-type (male)[2]
Dosage: 30 mg/kg; 60 mg/kg; 100 mg/kg
Administration: p.o.; single dose
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.
Animal Model: wild-type[2]
Dosage: 30 mg/kg
Administration: p.o.; single dose; pre-administered 30 minutes prior to Kyn
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%.
Animal Model: R6/2 transgenic, wild-type littermates (equal gender split, 4 weeks old)[2]
Dosage: 10 mg/kg; 30 mg/kg; 60 mg/kg; 100 mg/kg
Administration: p.o.; twice daily; 8 weeks
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.
Molecular Weight

290.70

Formula

C14H11ClN2O3
CAS No.
SMILES

O=C(C1=NC=NC(C2=CC(Cl)=C(OC3CC3)C=C2)=C1)O
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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CHDI-340246 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

CHDI-3402461426319-74-5CHDI340246CHDI 340246KMOKynurenine-3-monooxygenaseR6/2 mouse slicesstriatal SPNsHuntington's diseasehuman PBMCsprimary rat microgliaCHO cellstransgenic mouse modelskynurenine monooxygenaseQ175 heterozygous Huntington's disease model micecynomolgus monkey hepatocytesInhibitorinhibitorinhibit

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