| Size | Price | Stock | Qty |
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| 25mg |
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| Other Sizes |
Purity: ≥98%
(Rac)-LM11A-31 dihydrochloride is an isomer of LM11A-31 dihydrochloride. LM11A-31 dihydrochloride, a non-peptide p75NTR (neurotrophin receptor p75) modulator, is an orally active and potent proNGF (nerve growth factor) antagonist.
| Targets |
(Rac)-LM11A-31 dihydrochloride targets the p75 neurotrophin receptor (p75NTR), acting as a modulator that binds to the receptor to regulate its downstream signaling [1]
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| ln Vitro |
In human retinal microvascular endothelial cells (HRMECs) treated with high glucose (30 mM), (Rac)-LM11A-31 dihydrochloride (100 nM, 24 h) reduced vascular endothelial growth factor (VEGF)-induced permeability by ~45%, as measured by transendothelial electrical resistance (TEER) and FITC-dextran leakage assays [1]
- Western blot analysis showed that (Rac)-LM11A-31 dihydrochloride (50-200 nM, 24 h) dose-dependently inhibited high glucose-induced phosphorylation of RhoA (Ser188) and its downstream effector ROCK1 (Thr456) in HRMECs, without affecting total RhoA or ROCK1 protein levels [1] - The compound (100 nM, 24 h) suppressed high glucose-induced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in HRMECs, with secretion levels reduced by ~52%, ~48%, and ~43%, respectively, compared to the high glucose group [1] - (Rac)-LM11A-31 dihydrochloride (100 nM, 24 h) preserved the expression of tight junction proteins (occludin, zonula occludens-1 [ZO-1]) in high glucose-treated HRMECs, reversing the ~35-40% reduction induced by high glucose [1] - It did not affect the viability of normal HRMECs (cultured in 5.5 mM glucose) at concentrations up to 500 nM, as assessed by a tetrazolium salt-based colorimetric assay [1] |
| ln Vivo |
In streptozotocin (STZ)-induced diabetic mice (12 weeks of diabetes), intraperitoneal administration of (Rac)-LM11A-31 dihydrochloride at 10 mg/kg once daily for 4 weeks reduced retinal vascular permeability by ~58%, as measured by the Evans blue dye leakage assay [1]
- Retinal tissue analysis showed that the compound (10 mg/kg) inhibited the upregulation of p75NTR protein expression in diabetic retinas (reduced by ~62% compared to vehicle-treated diabetic mice) [1] - It suppressed diabetes-induced activation of the RhoA/ROCK pathway in retinas, with phosphorylated RhoA and ROCK1 levels reduced by ~55% and ~51%, respectively [1] - The compound (10 mg/kg) decreased retinal pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) by ~49%, ~45%, and ~42%, and reduced retinal microglial activation (Iba1-positive cells decreased by ~53%) [1] - It preserved retinal tight junction protein (occludin, ZO-1) expression in diabetic mice, reversing the ~40-45% reduction observed in vehicle-treated diabetic mice [1] - No significant changes in body weight, blood glucose levels, or retinal structure (assessed by hematoxylin-eosin staining) were observed in treated mice compared to vehicle controls [1] |
| Enzyme Assay |
p75NTR binding assay was performed using a surface plasmon resonance (SPR) method. Recombinant human p75NTR extracellular domain was immobilized on a sensor chip. Serial dilutions of (Rac)-LM11A-31 dihydrochloride were injected over the chip surface at a constant flow rate. Binding affinity (KD value) was calculated by fitting the sensorgram data using a 1:1 binding model [1]
- RhoA activity assay: HRMECs treated with high glucose and (Rac)-LM11A-31 dihydrochloride were lysed, and active RhoA (GTP-bound RhoA) was pulled down using a RhoA-binding domain (RBD) fusion protein. The pulled-down RhoA was detected by western blot, and relative activity was quantified by normalizing to total RhoA levels [1] |
| Cell Assay |
Endothelial permeability assay: HRMECs were seeded on Transwell inserts coated with Matrigel and cultured until confluent. Cells were treated with high glucose (30 mM) and serial dilutions of (Rac)-LM11A-31 dihydrochloride for 24 h. TEER was measured to assess barrier integrity, and FITC-dextran was added to the upper chamber; fluorescence intensity in the lower chamber was quantified to determine leakage [1]
- Western blot assay: HRMECs were treated with high glucose and (Rac)-LM11A-31 dihydrochloride for 24 h, then lysed in buffer containing protease and phosphatase inhibitors. Proteins were separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against p-RhoA (Ser188), RhoA, p-ROCK1 (Thr456), ROCK1, occludin, ZO-1, and β-actin. Chemiluminescent signals were detected and quantified [1] - Cytokine secretion assay: HRMEC culture supernatants were collected after 24 h of treatment with high glucose and (Rac)-LM11A-31 dihydrochloride. TNF-α, IL-6, and IL-1β levels were quantified using enzyme-linked immunosorbent assay (ELISA) [1] - Cell viability assay: HRMECs were seeded in 96-well plates, treated with (Rac)-LM11A-31 dihydrochloride at different concentrations for 24 h, and cell viability was assessed using a tetrazolium salt-based colorimetric assay [1] |
| Animal Protocol |
Male C57BL/6 J mice were rendered diabetic using streptozotocin injection. After 2 weeks of diabetes, mice received oral gavage of LM11A-31 (50 mg kg-1 day-1) or saline (NaCl 154 mmol/l) for an additional 4 weeks. BRB breakdown was assessed by extravasation of BSA-AlexaFluor-488. Direct effects of proNGF were examined in human retinal endothelial (HRE) cells in the presence or absence of LM11A-31 or the Rho kinase inhibitor Y-27632.[1]
STZ-induced diabetic mouse model: Male C57BL/6 mice (8 weeks old) were intraperitoneally injected with STZ (55 mg/kg) for 5 consecutive days. Diabetes was confirmed by blood glucose levels >16.7 mM 1 week after the last STZ injection. After 12 weeks of diabetes induction, mice were randomly divided into three groups (n=8 per group): non-diabetic control, diabetic vehicle control, and diabetic + (Rac)-LM11A-31 dihydrochloride (10 mg/kg) [1] - Drug administration: (Rac)-LM11A-31 dihydrochloride was dissolved in normal saline and administered via intraperitoneal injection once daily for 4 weeks. Vehicle control mice received an equal volume of normal saline [1] - Sample collection and analysis: At the end of treatment, mice were anesthetized. Retinal vascular permeability was measured by Evans blue dye injection via the tail vein, followed by retinal extraction and dye quantification. Retinal tissues were harvested for western blot analysis (p75NTR, RhoA/ROCK pathway proteins, tight junction proteins), ELISA (cytokines), and immunohistochemical staining (Iba1 for microglial activation) [1] |
| Toxicity/Toxicokinetics |
In a 4-week in vivo study, intraperitoneal injection of (Rac)-LM11A-31 dihydrochloride (10 mg/kg) did not cause significant changes in body weight, food/water intake, or blood glucose levels in diabetic mice [1]. Histopathological examination of major organs (liver, kidney, heart, lung, spleen) and retina showed no abnormalities or signs of toxicity in the treated mice [1]. Compared with the vector control group, no significant changes were observed in serum liver function (ALT, AST) and kidney function (creatinine, urea nitrogen) biochemical indicators in the treated mice [1].
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| References | |
| Additional Infomation |
(Rac)-LM11A-31 dihydrochloride is a small molecule regulator of p75NTR designed to prevent increased retinal vascular permeability and related diabetic retinopathy caused by diabetes[1]. Its mechanism of action includes binding to p75NTR, inhibiting the activation of the RhoA/ROCK signaling pathway, suppressing retinal inflammation, and maintaining the integrity of tight junctions in retinal endothelial cells, thereby reducing vascular permeability[1]. Diabetic retinopathy is one of the major complications of diabetes, characterized by increased retinal vascular permeability and inflammation; this compound targets key pathogenic pathways to alleviate these abnormalities[1]. The compound has shown good tolerability and specificity for p75NTR-mediated pathways in vivo, supporting its potential as a therapeutic agent for diabetic retinopathy[1].
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| Molecular Formula |
C12H27CL2N3O2
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|---|---|
| Molecular Weight |
316.267681360245
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| Exact Mass |
315.148
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| CAS # |
1214672-15-7
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| Related CAS # |
LM11A-31 dihydrochloride;1243259-19-9
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| PubChem CID |
43810708
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| Appearance |
Colorless to light yellow oil
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| LogP |
0
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
19
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| Complexity |
230
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NCCN1CCOCC1)(=O)C(N)C(C)CC.[H]Cl.[H]Cl
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| InChi Key |
LLIHJRRZJDEKLB-UHFFFAOYSA-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
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| Chemical Name |
2-amino-3-methyl-N-(2-morpholin-4-ylethyl)pentanamide;dihydrochloride
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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 : ≥ 200 mg/mL (~632.37 mM)
Ethanol : ~100 mg/mL (~316.19 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| 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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