LMP2-IN-1
LMP2-IN-1 is an orally bioavailable, brain-permeable macrocyclic peptide epoxyketone, acts as a selective and irreversible inhibitor of LMP2 (IC50 = 87 nM). LMP2-IN-1 rapidly distributes to the brain and forms an irreversible LMP2:AR-01 adduct. LMP2-IN-1 improves memory function and rescues reactive astrocytes in 5xFAD mouse models of Alzheimer's disease (AD).
For research use only. We do not sell to patients.
- CAS No.: 3056058-96-6
- Formula: C23H36FN3O6
- Molecular Weight:469.55
-
Storage:
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]
-
Biological Activity
-
Chemical Information
- Protocols
- Purity & Documentation
- References
-
Help & FAQs
Biological Activity
Description
Cellular Effect
|
Cell Line
|
Type | Value | Description | References |
|---|---|---|---|---|
| ARPE-19 | IC50 |
100 μM
Compound: 5
|
Cytotoxicity against human ARPE-19 cells assessed as reduction in cell viability incubated for 96 hrs by CellTiter 96 Aqueous One Solution Cell Proliferation Assay
Cytotoxicity against human ARPE-19 cells assessed as reduction in cell viability incubated for 96 hrs by CellTiter 96 Aqueous One Solution Cell Proliferation Assay
|
[PMID: 38636481] |
In Vitro
LMP2-IN-1 (compound AR-01) (0-500 nM; 24 h) dose-dependently inhibits LMP2 activity and forms LMP2:AR-01 adduct in murine microglial BV2 cells[1].
LMP2-IN-1 (compound 5) inhibits human 20S immunoproteasome LMP2 activity with an IC50 of 87 nM[2].
LMP2-IN-1 (10 μM; 120 min) shows high Caco2 cell permeability with an apparent permeability of 23.4 × 10^-6 cm/s and a low efflux ratio (ER) of 0.4[2].
LMP2-IN-1 (0.01-100 μM; 96 h) shows no cytotoxicity in normal human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells up to 30 μM and 100 μM, respectively[2].
LMP2-IN-1 (1 mg/mL, 4-fold serial dilution) is negative in the AMES test using S. typhimurium TA98 and TA100 strains with or without S9 fraction[2].
LMP2-IN-1 (2 μM; 4 h) exhibits a human plasma protein unbound fraction (fu) of 0.45 ± 0.07 as determined by equilibrium dialysis[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
-
Cell Line:BV2 cells
-
Concentration:0-500 nM
-
Incubation Time:24 h
-
Result:Inhibited LMP2 activity and formed LMP2:AR-01 adduct in a dose-dependent manner.
-
Cell Line:BV2 cells
-
Concentration:0-500 nM
-
Incubation Time:24 h
-
Result:Inhibited LMP2 activity and formed LMP2:AR-01 adduct in a dose-dependent manner.
-
Cell Line:human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells
-
Concentration:0.01-100 μM
-
Incubation Time:96 h
-
Result:Showed no cytotoxicity in normal human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells up to 30 μM and 100 μM, respectively.
Parmacokinetics
| Species | Dose | Route | Note | AUC0-last | AUCinf | Brain-Kp | C0 | Cmax | CL | F | T1/2 | Tmax | Vss |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 150 mg/kg | i.p. | plasma | 11000 ng/mL·h | NA ng/mL·h | NA | NA ng/mL | 29800 ng/mL | NA mL/h/kg | 53.8 % | 0.162 h | 0.25 h | NA mL/kg |
| Mice[2] | 150 mg/kg | p.o. | / | 3553 ng/mL·h | 3571 ng/mL·h | / | NA ng/mL | 3630 ng/mL | NA mL/h/kg | 9.8 % | 0.791 h | 0.333 h | NA mL/kg |
| Mice[2] | 40 mg/kg | i.v. | / | 9689 ng/mL·h | 9689 ng/mL·h | / | 31987 ng/mL | 25900 ng/mL | 4253 mL/h/kg | NA % | 0.420 h | 0.083 h | 2572 mL/kg |
| Mice[1] | 80 mg/kg | i.v. | plasma | 10900 ng/mL·h | 10900 ng/mL·h | NA | 94900 ng/mL | 41200 ng/mL | 7310 mL/h/kg | NA % | 0.710 h | 0.083 h | 7490 mL/kg |
| Mice[1] | 80 mg/kg | i.v. | brain | 185 ng/mL·h | 185 ng/mL·h | 0.0170 | NA ng/mL | 680 ng/mL | NA mL/h/kg | NA % | 0.137 h | 0.083 h | NA mL/kg |
| Rat[1] | 40 mg/kg | i.v. | plasma | 11500 ng/mL·h | 12150 ng/mL·h | NA | 67700 ng/mL | 52500 ng/mL | 3420 mL/h/kg | NA % | 0.459 h | 0.033 h | 2270 mL/kg |
In Vivo
LMP2-IN-1 (150 mg/kg; i.p.; single dose) achieves approximately 54% bioavailability and complete LMP2:AR-01 adduct formation in the mouse brain at 6 h postdose in healthy BALB/c mice (male, 7 weeks old)[1].
LMP2-IN-1 (150 mg/kg; p.o.; single dose) achieves approximately 10% oral bioavailability and approximately 71% LMP2:AR-01 adduct formation in the mouse brain in healthy BALB/c mice (male, 7 weeks old)[1].
LMP2-IN-1 (20 mg/kg; i.p.; twice weekly for 3 weeks) achieves cumulative brain LMP2 occupancy (approximately 46% adduct formation at day 21) in aged C57BL/6 mice (female, 8 months old)[1].
LMP2-IN-1 (20 mg/kg; i.p.; twice weekly for 3 weeks) improves spatial memory performance and rescues reactive astrocytes in 5xFAD mice (4 months old, both sexes)[1].
LMP2-IN-1 (compound 5) (150 mg/kg; p.o.; single dose) inhibits approximately 90% of blood LMP2 activity and 21% of brain LMP2 activity at 6 h postdose in healthy BALB/c mice (male, 7 weeks old)[2].
LMP2-IN-1 (40 mg/kg; i.v.; single dose) is detected in brain, liver, kidney, and spleen at 2 h postdose, but not detected in lung tissues in healthy BALB/c mice (male, 7 weeks old)[2].
LMP2-IN-1 (5-100 mg/kg; i.v.; single dose) shows no apparent toxic effects in healthy BALB/c mice (male, 7 weeks old) during a 72 h observation period[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
-
Dosage:80 mg/kg
-
Administration:i.v.; single dose
-
Result:Distributed to the mouse brain with a brain-to-plasma partition coefficient of 0.017.
Achieved complete LMP2:AR-01 adduct formation and approximately 70% LMP2 activity inhibition in the brain within 5 min postdose.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
-
Dosage:150 mg/kg
-
Administration:i.p.; single dose
-
Result:Achieved approximately 54% bioavailability and complete LMP2:AR-01 adduct formation in the mouse brain at 6 h postdose.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
-
Dosage:150 mg/kg
-
Administration:p.o.; single dose
-
Result:Achieved approximately 10% oral bioavailability and approximately 71% LMP2:AR-01 adduct formation in the mouse brain.
-
Animal Model:Aged C57BL/6 mice (female, 8 months old)[1]
-
Dosage:20 mg/kg
-
Administration:i.p.; twice weekly for 3 weeks
-
Result:Achieved cumulative brain LMP2 occupancy (approximately 46% adduct formation at day 21).
-
Animal Model:5xFAD mice (4 months old, both sexes)[1]
-
Dosage:20 mg/kg
-
Administration:i.p.; twice weekly for 3 weeks
-
Result:Improved spatial memory performance and rescued reactive astrocytes.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
-
Dosage:150 mg/kg
-
Administration:p.o.; single dose
-
Result:Inhibited approximately 90% of blood LMP2 activity and 21% of brain LMP2 activity at 6 h postdose.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
-
Dosage:40 mg/kg
-
Administration:i.v.; single dose
-
Result:Could be detected in brain, liver, kidney, and spleen at 2 h postdose, but could not detected in lung tissues.
-
Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
-
Dosage:5-100 mg/kg
-
Administration:i.v.; single dose
-
Result:Showed no apparent toxic effects during a 72 h observation period.
Chemical Information
-
CAS No. 3056058-96-6
-
Molecular Weight 469.55
-
Formula C23H36FN3O6
-
SMILES
F[C@@H]1C[C@@H](C(N[C@@H](COCCCCCC2=O)C(N[C@@H](CC(C)C)C([C@]3(C)OC3)=O)=O)=O)N2C1
-
Shipping
Room temperature in continental US; may vary elsewhere.
-
Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocols
-
Alzheimer’s Disease Modeling
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive functions and loss of specific types of neurons and synapses. Alzheimer's symptoms can be simulated in mice by injecting drugs (such as Aβ) or genetically modified.
Purity & Documentation
References
[1]. Thapa Magar TB, et al. Pharmacokinetics, Target Engagement of an Immunoproteasome Subunit Low-Molecular-Mass Polypeptide 2 (LMP2) Inhibitor AR-01, and Its Anti-Alzheimer's Effects in Rodents. ACS Pharmacol Transl Sci. 2026 Jun 29;9(7):1869-1880. [Content Brief]
[2]. Park JE, et al. Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease. J Med Chem. 2024 May 9;67(9):7146-7157. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
LMP2-IN-1 Related Classifications
HY-184919 Related Classifications
Powered by Bioz