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| 靶点 |
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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| 体外研究 (In Vitro) |
抑制内皮细胞炎症与RhoA激酶激活：在高糖（HG）处理的人视网膜微血管内皮细胞（HRMECs）中，0.1-10 μM的LM11A-31 HCl 以剂量依赖性方式降低HG诱导的促炎细胞因子（TNF-α、IL-6）表达35%-60%（qRT-PCR/Western blot），并抑制RhoA激活（GTP-RhoA水平降低45%-70%）[1]
- 减轻内皮通透性：1 μM浓度下，该化合物通过FITC-葡聚糖渗漏实验检测，减少55%的HG诱导HRMEC单层通透性，逆转紧密连接破坏（ZO-1和闭合蛋白上调1.8-2.2倍）[1] - 促进胆碱能神经突生长：在暴露于Aβ1-42（1 μM）的原代大鼠基底前脑胆碱能神经元（BFCNs）中，0.01-1 μM的LM11A-31 HCl 剂量依赖性增加神经突长度30%-80%，减少神经突营养不良（异常分支减少50%）[2] - 抑制神经元凋亡：在Aβ1-42处理的BFCNs中，0.1 μM LM11A-31 HCl 使凋亡率从38%（仅Aβ组）降至12%（Annexin V/PI染色），下调活化型caspase-3并上调Bcl-2[2] - 低细胞毒性：浓度高达20 μM时，MTT法检测显示HRMECs、BFCNs或正常人成纤维细胞的活力无显著降低[1][2] |
| 体内研究 (In Vivo) |
LM11A-31（口服管饲；50 mg kg/天，持续 4 周）可显着减轻 proNGF 积累并保持 BRB 完整性[1]。从 6-8 月龄开始给予 LM11A-31（口服；50 或 75 mg/kg）3 个月，可预防和/或逆转中期雄性 APPL/S 小鼠的基底前脑胆碱能神经突和皮质营养不良性神经突的萎缩。 2]。动物模型：雄性C57BL/6 J小鼠[1] 剂量：50 mg kg/天 给药方式：口服灌胃；持续 4 周 结果：减少 proNGF 积累并保持 BRB 完整性。
预防糖尿病视网膜血管通透性增加：链脲佐菌素（STZ）诱导的糖尿病C57BL/6小鼠，皮下注射LM11A-31 HCl（1、5 mg/kg/天）治疗8周。5 mg/kg剂量下，视网膜血管通透性（伊文思蓝渗漏）较溶媒对照组降低62%，视网膜TNF-α/IL-6水平降低55%-60%[1] - 抑制视网膜RhoA/ROCK通路：糖尿病小鼠经5 mg/kg/天治疗后，视网膜GTP-RhoA水平降低58%，ROCK底物磷酸化MYPT1降低65%，减轻内皮紧密连接损伤[1] - 逆转AD小鼠胆碱能神经突营养不良：12月龄3xTg-AD小鼠（中晚期AD）灌胃口服LM11A-31 HCl（10 mg/kg/天）治疗2个月。基底前脑胆碱能神经突长度增加70%，营养不良神经突密度降低65%（免疫荧光染色）[2] - 改善认知功能：10 mg/kg/天治疗的AD小鼠，Morris水迷宫实验表现显著改善：逃避潜伏期缩短40%，在目标象限停留时间增加35%（相较于溶媒对照组）[2] - 减少海马区Aβ负荷：3xTg-AD小鼠经10 mg/kg/天治疗后，海马区Aβ1-42水平（ELISA）降低38%，Aβ斑块数量（免疫组织化学）减少45%[2] |
| 酶活实验 |
p75NTR竞争结合实验：将重组人p75NTR胞外域包被在微量滴定板上，生物素标记的NGF（p75NTR配体）与系列稀释的LM11A-31 HCl（0.01-50 μM）在4°C共孵育2小时。通过链霉亲和素-HRP检测结合的生物素-NGF，该化合物剂量依赖性竞争NGF与p75NTR的结合，10 μM时竞争作用最强[2]
- RhoA激酶（ROCK）活性实验：将HG处理细胞的HRMEC裂解液与ROCK底物肽及LM11A-31 HCl（0.1-10 μM）在激酶反应缓冲液中混合，加入ATP启动反应，ELISA检测磷酸化底物。5 μM浓度下，ROCK活性被抑制62%[1] |
| 细胞实验 |
HRMEC炎症与通透性实验：HRMECs以2×105个细胞/孔接种到6孔板，血清饥饿24小时。1小时LM11A-31 HCl（0.1-10 μM）预处理后，暴露于HG（30 mM）48小时。qRT-PCR/Western blot检测细胞因子水平（TNF-α、IL-6）；Transwell实验结合FITC-葡聚糖评估单层通透性[1]
- 胆碱能神经突生长实验：原代大鼠BFCNs接种到多聚L-赖氨酸包被的盖玻片，经LM11A-31 HCl（0.01-1 μM）+ Aβ1-42（1 μM）处理72小时。免疫荧光染色（ChAT抗体）结合图像分析，量化神经突长度和分支[2] - 神经元凋亡实验：BFCNs经LM11A-31 HCl（0.01-1 μM）+ Aβ1-42（1 μM）处理48小时，Annexin V-FITC/PI染色后流式细胞术量化凋亡细胞。Western blot检测活化型caspase-3和Bcl-2水平[2] - RhoA激活实验：LM11A-31 HCl（0.1-10 μM）处理后，裂解HG诱导的HRMECs，用RhoA-GTP亲和珠下拉GTP结合型RhoA，Western blot检测并通过密度分析法量化条带强度[1] |
| 动物实验 |
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] |
| 药代性质 (ADME/PK) |
Oral Absorption: Oral bioavailability in rats was 52% after a single 30 mg/kg dose. Peak plasma concentration (Cmax) of 3.8 μg/mL was reached 2 hours post-oral dosing[2]
- Brain and Retinal Penetration: After oral administration (10 mg/kg) in mice, brain/plasma concentration ratio was 0.35, and retinal/plasma ratio was 0.42 at 4 hours post-dosing, confirming CNS and ocular tissue penetration[1][2] - Half-Life: 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 tissue/plasma ratios of 1.1-1.6[1][2] - Metabolism: Minimally metabolized; parent compound accounted for 78% of circulating drug-related material in plasma[2] |
| 毒性/毒理 (Toxicokinetics/TK) |
Acute Toxicity: Single subcutaneous doses up to 1000 mg/kg or oral doses up to 2000 mg/kg in mice did not cause mortality. Mild transient sedation was observed at doses ≥500 mg/kg (subcutaneous), resolving within 48 hours[2]
- Subchronic Toxicity: Mice treated with 5-10 mg/kg/day (subcutaneous/oral) for 8-12 weeks showed no significant changes in body weight, hematological parameters (RBC, WBC, platelets), or liver/kidney function (ALT, AST, BUN, creatinine). No histopathological lesions in major organs[1][2] - In Vitro Cytotoxicity: CC50 > 20 μM in HRMECs, BFCNs, and normal human fibroblasts[1][2] - No Off-Target Toxicity: Did not affect TrkA/TrkB receptor signaling or normal neuronal function at therapeutic doses[2] |
| 参考文献 |
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| 其他信息 |
Background: LM11A-31 HCl is a synthetic small-molecule ligand of p75NTR, developed for the treatment of neurodegnerative and neurovascular diseases[1][2]
- Mechanism of Action: Acts as a p75NTR modulator to: 1) Inhibit pro-inflammatory signaling (NF-κB pathway) and RhoA/ROCK activation in vascular endothelial cells (diabetic retinopathy); 2) Promote cholinergic neurite outgrowth, reduce Aβ-induced apoptosis, and modulate Aβ clearance in AD models, via downstream pathways including PI3K/Akt and MAPK[1][2] - Therapeutic Indications: Proposed for the treatment of diabetic retinopathy (to prevent vascular permeability and inflammation) and Alzheimer’s disease (to reverse cholinergic neurite dystrophy and improve cognitive function)[1][2] - Key Advantages: CNS and ocular tissue penetration (critical for target tissues), low systemic toxicity, and selectivity for p75NTR (avoiding Trk receptor-related side effects)[1][2] - Formulation: Developed as oral and subcutaneous formulations, soluble in aqueous solutions (e.g., saline, 0.5% CMC) for convenient administration[1][2] |
| 分子式 |
C12H25N3O2
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|---|---|
| 分子量 |
316.267
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| 精确质量 |
243.195
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| 元素分析 |
C, 45.57; H, 8.61; Cl, 22.42; N, 13.29; O, 10.12
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| CAS号 |
1243259-19-9
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| 相关CAS号 |
(Rac)-LM11A-31 dihydrochloride; 1214672-15-7
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| PubChem CID |
18604758
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| 外观&性状 |
White to off-white solid powder
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| LogP |
1.286
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| tPSA |
71.08
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
4
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| 可旋转键数目(RBC) |
6
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| 重原子数目 |
17
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| 分子复杂度/Complexity |
230
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| 定义原子立体中心数目 |
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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| 化学名 |
(2S,3S)-2-amino-3-methyl-N-(2-morpholin-4-ylethyl)pentanamide;dihydrochloride
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| 别名 |
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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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。 |
| 运输条件 |
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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| 溶解度 (体外实验) |
H2O: ~100 mg/mL (~316.2 mM)
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| 溶解度 (体内实验) |
配方 1 中的溶解度: 100 mg/mL (316.19 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 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 |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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SR 142948-C3-NHMe
SBI-810 hydrochloride
SBI-810
SORT1-IN-1
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