NLRP3-IN-93
NLRP3-IN-93 is an orally active, blood-brain barrier-permeable NLRP3 inhibitor. NLRP3-IN-93 binds to the NACHT domain, blocks inflammasome assembly, and inhibits downstream IL-1β release, without significantly inhibiting various CYP isoforms. NLRP3-IN-93 demonstrates dose-dependent efficacy in mouse models of acute inflammation and Parkinson's disease, and exhibits good tolerability and an acceptable safety window in rats and dogs. NLRP3-IN-93 can be used in research on Parkinson's disease.
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- CAS No.: 3055155-53-5
- Formule: C19H24N6O
- Masse moléculaire:352.43
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Stockage:
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
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
IC50 & Target
[1]|
NLRP3 |
IL-1β 18 nM (IC50, THP-1 cells) |
IL-1β 11 nM (IC50, human whole blood) |
IL-1β 73 nM (IC50, mouse whole blood) |
In Vitro
NLRP3-IN-93 (Compound 25) (30 min pre-incubation + 1 h Nigericin (HY-127019)) exhibits significant IL-1β inhibitory activity in nigericin-stimulated THP-1 cells, with an IC50 of 18 nM[1].
NLRP3-IN-93 (30 min pre-incubation + 3 h Lipopolysaccharide (HY-D1056A1) + 1 h Adenosine triphosphate (HY-B2176) stimulation) exhibits significant IL-1β inhibitory activity in LPS/ATP-stimulated human whole blood, with an IC50 of 11 nM[1].
NLRP3-IN-93 (6.86-5000 nM; 30 min pre-incubation + 3 h LPS + 1 h Adenosine triphosphate stimulation) exhibits IL-1β inhibitory activity in LPS/ATP-stimulated mouse whole blood, with an IC50 of 73 nM[1].
NLRP3-IN-93 (0.01-30 μM) shows no significant inhibition against CYP3A4 (M/T), 2C9, 2C19, 2D6, and 1A2 isoforms (IC50 > 30 μM)[1].
NLRP3-IN-93 (0.3-30 μM) shows weak inhibitory activity against the hERG potassium channel, with an IC50 of 16 μM[1].
NLRP3-IN-93 (2 μM; 2 h) exhibits high permeability in the Caco-2 cell monolayer model (Papp A-B = 14.6 × 10-6 cm/s; Papp B-A = 32.6 × 10-6 cm/s), with a low efflux ratio (Efflux Ratio = 2.2)[1].
NLRP3-IN-93 (2.5 μL of 100 μM; 0.5-60 min) demonstrates good metabolic stability in liver microsomes across human and multiple animal species (T1/2: human >184 min, mouse 184 min, rat 184 min, dog >85 min, monkey >59 min)[1].
NLRP3-IN-93 (6 h) shows moderate plasma protein binding (human 65%, monkey 68%, dog 65%, rat 58%, mouse 61%) and high brain tissue binding (mouse 85%, rat 85%, monkey 86%)[1].
NLRP3-IN-93 (10 μM) shows no significant effects on 78 safety panel targets (receptors, enzymes, ion channels) and 58 kinase panel targets[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | CL | AUC | T1/2 | F | Cmax |
|---|---|---|---|---|---|---|---|
| Cynomolgus Monkey[1] | 0.5 mg/kg | i.v. | 37 mL/min/kg | 670 ng·h/mL | 2.5 h | / | / |
| Cynomolgus Monkey[1] | 2 mg/kg | p.o. | / | 670 ng·h/mL | 2.5 h | 70 % | 150 ng/mL |
| Dog[1] | 0.5 mg/kg | i.v. | 13 mL/min/kg | 2224 ng·h/mL | 4.8 h | / | / |
| Dog[1] | 2 mg/kg | p.o. | / | 2224 ng·h/mL | 4.8 h | 85 % | 240 ng/mL |
| Mice[1] | 1 mg/kg | i.v. | 36 mL/min/kg | 830 ng·h/mL | 1.6 h | / | / |
| Mice[1] | 2 mg/kg | p.o. | / | 830 ng·h/mL | 1.6 h | 92 % | 410 ng/mL |
| Rat[1] | 1 mg/kg | i.v. | 25 mL/min/kg | 910 ng·h/mL | 3.1 h | / | / |
| Rat[1] | 2 mg/kg | p.o. | / | 910 ng·h/mL | 3.1 h | 72 % | 210 ng/mL |
In Vivo
NLRP3-IN-93 (12.5-50 mg/kg; p.o.; twice daily; for 14 days) dose-dependently improves motor function in the MPTP (HY-15608)-induced subacute Parkinson's disease mouse model, including reduced beam traversal time and pole descent time[1].
NLRP3-IN-93 (50-300 mg/kg/day; p.o.; once daily; for 14 days) in repeat-dose toxicity studies in SD rats and Beagle dogs, induces hematological changes and minimally increased alveolar macrophage density in the lungs in rats at mid and high doses, and induces hematological and serum biochemical changes accompanied by minimal to mild thymic atrophy in dogs at the high dose. No adverse effects are observed at the mid-dose, indicating an acceptable safety window[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male C57BL/6 mice received an intraperitoneal (i.p.) injection of 1 μg E. coli 055/B5 ultrapure lipopolysaccharide (HY-D1056) (LPS), followed 2 h later by an i.p. injection of 0.5 mL of 30 mM adenosine triphosphate (HY-B2176) (ATP) disodium salt (pH 7.2) [1].
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Dosage:3, 10 mg/kg
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Administration:Oral gavage (p.o.), single dose, administered 1 h prior to LPS injection
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Result:Dose-dependently inhibited IL-1β production in the peritoneal lavage fluid, with 98% inhibition observed at 10 mg/kg.
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Animal Model:Male C57BL/6 mice were intraperitoneally (i.p.) injected with MPTP (HY-15608) at 30 mg/kg for five consecutive days to induce the Parkinson's disease model. [1]
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Dosage:12.5, 25, 50 mg/kg
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Administration:Oral gavage (p.o.), twice daily for 14 days
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Result:Dose-dependently improved motor function in MPTP-induced mice, as evidenced by shortened beam traversal time and pole descent time at 50 mg/kg, the effective dose with a corresponding exposure level of 17,500 h·ng/mL.
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Animal Model:Sprague-Dawley rats (7-8 weeks old), 5 males and 5 females per group [1].
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Dosage:100, 200, 300 mg/kg/day
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Administration:Oral gavage (p.o.), once daily for 14 days
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Result:Hematology: Increases in NEUT#, MONO#, NEUT%, and MONO% were observed in males at 200 and 300 mg/kg/day and in females at 300 mg/kg/day.
Histopathology: Minimally increased alveolar macrophage density in the lungs was observed at 200 and 300 mg/kg/day.
No compound-related changes were noted in hematology, serum biochemistry, or histopathology at 100 mg/kg/day.
The no observed adverse effect level (NOAEL) was established at 100 mg/kg/day, with a corresponding AUC exposure of 112,000 ng•h/mL.
The therapeutic index (NOAEL AUC / efficacy exposure) was calculated as 6 (112,000 / 17,500).
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Animal Model:Beagle dogs, 2 males and 2 females per group. [1].
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Dosage:50, 100, 200 mg/kg/day
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Administration:Oral administration via porcine hard gelatin capsules, once daily for 14 days
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Result:Hematological and serum biochemical changes (decreased RET#/RET% and elevated BUN) were observed at 200 mg/kg/day.
Minimal to mild thymic atrophy was noted in the 200 mg/kg/day group.
No compound-related changes were noted in hematology, serum biochemistry, or histopathology at 100 mg/kg/day.
The no observed adverse effect level (NOAEL) was established at 100 mg/kg/day, with a corresponding AUC exposure of 78,900 h·ng/mL.
The therapeutic index (NOAEL AUC / efficacy exposure) was calculated as 5 (78,900 / 17,500).
Chemical Information
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CAS No. 3055155-53-5
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Masse moléculaire 352.43
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Formule C19H24N6O
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SMILES
CC1=C(C2=NC3=NC(N[C@H]4CN(C)CCC4)=NN3C=C2)C(O)=CC(C)=C1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
NLRP3-IN-93 Related Classifications
HY-184651 Related Classifications
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Keywords
- NLRP3-IN-93
- 3055155-53-5
- NOD-like Receptor (NLR)
- Interleukin Related
- NLRP3-IN-93,NLRP3 inhibitor
- NLRP3
- orally activity
- brain-penetrant
- blood-brain barrier
- NLRP3 inflammasome
- NACHT domain
- LPS/ATP
- IL-1β
- IL-1 beta
- interleukin-1 beta
- Parkinson's disease
- THP-1 cells
- Caco-2
- HEK 293
- hERG
- CYP
- CYP3A4
- CYP2C9
- CYP2C19
- CYP2D6
- CYP1A2
- liver microsomal stability
- acute peritonitis model
- MPTP
- MPTP-induced Parkinson's disease model
- C57BL/6 mice
- SD rat
- Sprague-Dawley rat
- Beagle dog
- central nervous system
- small molecule inhibitor
- Inhibitor
- inhibitor
- inhibit