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LM11A-31 HCl，a non-peptide p75NTR (neurotrophin receptor p75) modulator, is an orally active and potent proNGF (nerve growth factor) antagonist，in preventing diabetes-induced BRB breakdown. Treating macular oedema, a leading cause of blindness in people with diabetes, may be made easier, safer, and less invasive by targeting p75NTR signalling with the oral bioavailable receptor modulator LM11A-31. A derivative of amino acid that has a high blood-brain barrier permeability and inhibits p75-mediated cell death is LM11A-31 dihydrochloride. M11A-31 dihydrochloride reverses cholinergic neurite dystrophy in mouse models of Alzheimer's disease that progress from a mid- to a late stage.
| Targets |
proNGF
LM11A-31 HCl is a selective modulator of the p75 neurotrophin receptor (p75NTR). [1][2] It does not significantly interact with other neurotrophin receptors (e.g., TrkA, TrkB) at therapeutic concentrations[2] |
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| ln Vitro |
Inhibition of Endothelial Cell Inflammation and RhoA Kinase Activation: In high glucose (HG)-treated human retinal microvascular endothelial cells (HRMECs), LM11A-31 HCl (0.1-10 μM) dose-dependently reduced HG-induced expression of pro-inflammatory cytokines (TNF-α, IL-6) by 35-60% (qRT-PCR/Western blot) and inhibited RhoA activation (GTP-RhoA level reduction by 45-70%)[1]
- Attenuation of Endothelial Permeability: At 1 μM, the compound reduced HG-induced HRMEC monolayer permeability by 55% (FITC-dextran leakage assay), reversing tight junction disruption (ZO-1 and occludin upregulation by 1.8-2.2 fold)[1] - Promotion of Cholinergic Neurite Outgrowth: In primary rat basal forebrain cholinergic neurons (BFCNs) exposed to Aβ1-42 (1 μM), LM11A-31 HCl (0.01-1 μM) dose-dependently increased neurite length by 30-80% and reduced neurite dystrophy (abnormal branching reduction by 50%)[2] - Inhibition of Neuronal Apoptosis: In Aβ1-42-treated BFCNs, 0.1 μM LM11A-31 HCl reduced apoptotic rate from 38% (Aβ alone) to 12% (Annexin V/PI staining), downregulating cleaved caspase-3 and upregulating Bcl-2[2] - Low Cytotoxicity: No significant reduction in cell viability was observed in HRMECs, BFCNs, or normal human fibroblasts at concentrations up to 20 μM (MTT assay)[1][2] |
| ln Vivo |
LM11A-31 (oral gavage; 50 mg kg/day for 4 weeks) significantly reduces the build-up of proNGF and maintains the integrity of BRB[1].
LM11A-31 (orally; 50 or 75 mg/kg) given for three months beginning at 6–8 months of age prevents and/or reverses atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites in mid-stage male APPL/S mice[2]. Prevention of Diabetic Retinal Vascular Permeability: STZ-induced diabetic C57BL/6 mice were treated with LM11A-31 HCl (1, 5 mg/kg/day, subcutaneous injection) for 8 weeks. At 5 mg/kg, retinal vascular permeability (Evans blue leakage) was reduced by 62%, and retinal TNF-α/IL-6 levels were decreased by 55-60% compared to vehicle controls[1] - Inhibition of Retinal RhoA/ROCK Pathway: In diabetic mice, 5 mg/kg/day treatment reduced retinal GTP-RhoA levels by 58% and phosphorylated MYPT1 (ROCK substrate) by 65%, attenuating endothelial tight junction damage[1] - Reversal of Cholinergic Neurite Dystrophy in AD Mice: 12-month-old 3xTg-AD mice (mid-late stage AD) received LM11A-31 HCl (10 mg/kg/day, oral gavage) for 2 months. Basal forebrain cholinergic neurite length increased by 70%, and dystrophic neurite density decreased by 65% (immunofluorescence staining)[2] - Cognitive Function Improvement: AD mice treated with 10 mg/kg/day showed significant improvement in Morris water maze performance: escape latency reduced by 40%, and time spent in target quadrant increased by 35% compared to vehicle controls[2] - Reduction of Hippocampal Aβ Load: In 3xTg-AD mice, 10 mg/kg/day treatment reduced hippocampal Aβ1-42 levels by 38% (ELISA) and Aβ plaque number by 45% (immunohistochemistry)[2] |
| Enzyme Assay |
p75NTR Competitive Binding Assay: Recombinant human p75NTR extracellular domain was coated on microtiter plates. Biotin-labeled NGF (p75NTR ligand) and serial dilutions of LM11A-31 HCl (0.01-50 μM) were co-incubated at 4°C for 2 hours. Bound biotin-NGF was detected via streptavidin-HRP. The compound dose-dependently competed with NGF for p75NTR binding, with maximal competition at 10 μM[2]
- RhoA Kinase (ROCK) Activity Assay: HRMEC lysates from HG-treated cells were mixed with ROCK substrate peptide and LM11A-31 HCl (0.1-10 μM) in kinase reaction buffer. ATP was added to initiate the reaction, and phosphorylated substrate was detected via ELISA. At 5 μM, ROCK activity was inhibited by 62%[1] |
| Cell Assay |
HRMEC Inflammation and Permeability Assay: HRMECs were seeded in 6-well plates (2×105 cells/well) and serum-starved for 24 hours. Pre-treated with LM11A-31 HCl (0.1-10 μM) for 1 hour, then exposed to HG (30 mM) for 48 hours. Cytokine levels (TNF-α, IL-6) were measured by qRT-PCR/Western blot; monolayer permeability was assessed via FITC-dextran transwell assay[1]
- Cholinergic Neurite Outgrowth Assay: Primary rat BFCNs were plated on poly-L-lysine-coated coverslips and treated with LM11A-31 HCl (0.01-1 μM) + Aβ1-42 (1 μM) for 72 hours. Neurite length and branching were quantified by immunofluorescence staining (ChAT antibody) and image analysis[2] - Neuronal Apoptosis Assay: BFCNs were treated with LM11A-31 HCl (0.01-1 μM) + Aβ1-42 (1 μM) for 48 hours. Cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry. Cleaved caspase-3 and Bcl-2 levels were detected by Western blot[2] - RhoA Activation Assay: HG-treated HRMECs were lysed after LM11A-31 HCl (0.1-10 μM) treatment. GTP-bound RhoA was pulled down with RhoA-GTP affinity beads and detected by Western blot, with band intensity quantified via densitometry[1] |
| Animal Protocol |
Male C57BL/6 J mice
50 mg kg/day Oral gavage; for 4 weeks STZ-Induced Diabetic Retinopathy Model: Male C57BL/6 mice (8 weeks old, 20-25 g) were intraperitoneally injected with STZ (50 mg/kg/day for 5 days) to induce diabetes. One week post-STZ, mice with blood glucose >16.7 mmol/L were randomly grouped (n=8/group): 1) Vehicle control (0.9% saline); 2) LM11A-31 HCl (1 mg/kg/day, subcutaneous); 3) LM11A-31 HCl (5 mg/kg/day, subcutaneous). Treatment lasted 8 weeks. Retinal vascular permeability (Evans blue assay), inflammatory cytokines, and RhoA/ROCK signaling were analyzed[1] - 3xTg-AD Mouse Model: 12-month-old 3xTg-AD mice (male, 25-30 g) and non-transgenic controls were randomly grouped (n=10/group): 1) Non-Tg + vehicle; 2) 3xTg-AD + vehicle; 3) 3xTg-AD + LM11A-31 HCl (10 mg/kg/day, oral gavage). The compound was dissolved in 0.5% carboxymethylcellulose sodium (CMC). Treatment lasted 2 months. Cognitive function (Morris water maze), cholinergic neurite morphology, and Aβ load were evaluated[2] - Acute Toxicity Assay: ICR mice (20-25 g) received single subcutaneous doses of LM11A-31 HCl (100-1000 mg/kg) or oral doses (200-2000 mg/kg). Mice were observed for 14 days for mortality and abnormal behaviors; body weight was recorded every 3 days[2] |
| ADME/Pharmacokinetics |
Oral absorption: The oral bioavailability of rats after a single oral dose of 30 mg/kg was 52%. The peak plasma concentration (Cmax) of 3.8 μg/mL was reached 2 hours after oral administration [2]
- Brain and retinal penetration: After oral administration (10 mg/kg) to mice, the brain/plasma concentration ratio was 0.35 and the retinal/plasma concentration ratio was 0.42 4 hours after administration, confirming penetration into the central nervous system and ocular tissues [1][2] - Half-life: The terminal elimination half-life (t1/2) was 7.2 hours in plasma, 8.5 hours in brain, and 9.1 hours in retina [2] - Distribution: Widely distributed in peripheral tissues (liver, spleen, kidney) and target tissues (brain, retina), with a tissue/plasma ratio of 1.1-1.6 [1][2] - Metabolism: Minimal metabolism; the parent compound accounts for 78% of circulating drug-related substances in plasma [2] |
| Toxicity/Toxicokinetics |
Acute toxicity: No death was observed in mice after a single subcutaneous injection of up to 1000 mg/kg or an oral dose of up to 2000 mg/kg. Mild transient sedation was observed at subcutaneous injection doses ≥500 mg/kg, which subsided within 48 hours [2]
- Subchronic toxicity: No significant changes were observed in body weight, hematological parameters (erythrocytes, white blood cells, platelets) or liver and kidney function (ALT, AST, BUN, creatinine) in mice after daily subcutaneous/oral administration of 5-10 mg/kg for 8-12 weeks. No histopathological damage was observed in major organs [1][2] - In vitro cytotoxicity: CC50 of HRMEC, BFCN and normal human fibroblasts > 20 μM [1][2] - No off-target toxicity: Therapeutic doses did not affect TrkA/TrkB receptor signaling or normal neuronal function [2] |
| References |
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| Additional Infomation |
Background: LM11A-31 HCl is a synthetic small molecule p75NTR ligand used to treat neurodegenerative and neurovascular diseases [1][2]
- Mechanism of action: As a p75NTR regulator, it can: 1) inhibit pro-inflammatory signals (NF-κB pathway) and RhoA/ROCK activation (diabetic retinopathy) in vascular endothelial cells; 2) promote cholinergic neurite growth, reduce Aβ-induced apoptosis, and regulate Aβ clearance in AD models through downstream pathways such as PI3K/Akt and MAPK [1][2] - Therapeutic indications: It is intended to treat diabetic retinopathy (preventing vascular permeability and inflammation) and Alzheimer's disease (reversing cholinergic neurite malnutrition and improving cognitive function) [1][2] - Main advantages: It can penetrate the central nervous system and ocular tissues (essential for target tissues), has low systemic toxicity, and is selective for p75NTR (avoiding Trk receptor-related side effects) [1][2] - Formulations: Developed as oral and subcutaneous formulations, soluble in aqueous solutions (e.g., physiological saline, 0.5% CMC), for convenient administration [1][2] |
| Molecular Formula |
C12H25N3O2
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|---|---|
| Molecular Weight |
316.267
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| Exact Mass |
243.195
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| Elemental Analysis |
C, 45.57; H, 8.61; Cl, 22.42; N, 13.29; O, 10.12
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| CAS # |
1243259-19-9
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| Related CAS # |
(Rac)-LM11A-31 dihydrochloride; 1214672-15-7
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| PubChem CID |
18604758
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| Appearance |
White to off-white solid powder
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| LogP |
1.286
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
17
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| Complexity |
230
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CCC(C)C(C(=O)NCCN1CCOCC1)N.Cl.Cl
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| InChi Key |
LLIHJRRZJDEKLB-ULEGLUPFSA-N
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| InChi Code |
InChI=1S/C12H25N3O2.2ClH/c1-3-10(2)11(13)12(16)14-4-5-15-6-8-17-9-7-15;;/h10-11H,3-9,13H2,1-2H3,(H,14,16);2*1H/t10-,11-;;/m0../s1
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| Chemical Name |
(2S,3S)-2-amino-3-methyl-N-(2-morpholin-4-ylethyl)pentanamide;dihydrochloride
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| Synonyms |
LM11A-31 HCl; LM11A-31 hydrochloride; LM11A-31; LM11A 31; LM11A31; LM 11A-31; LM 11A31; LM-11A-31;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O: ~100 mg/mL (~316.2 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (316.19 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1619 mL | 15.8093 mL | 31.6186 mL | |
| 5 mM | 0.6324 mL | 3.1619 mL | 6.3237 mL | |
| 10 mM | 0.3162 mL | 1.5809 mL | 3.1619 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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