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| 靶点 |
LY2811376 specifically targets β-site amyloid precursor protein cleaving enzyme 1 (BACE1) (Ki = 0.7 nM; IC50 = 1.3 nM) [1]
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| 体外研究 (In Vitro) |
LY2811376 治疗导致过度表达 APP 的人胚胎肾细胞系中 Aβ 释放呈浓度依赖性减少；半最大有效浓度 (EC50) 约为 300 nM。当 LY2811376 给予 PDAPP 转基因小鼠原代神经元细胞时，Aβ 产量以浓度依赖性方式减少，EC50 约为 100 nM[1]。 LY2811376 表现出良好的 ADME 特性和选择性（BACE1 IC50=240 nM，细胞效力 IC50=300 nM，组织蛋白酶 D 选择性：分别约为 10 倍和 65 倍）[3]。 LY2811376 以剂量依赖性方式降低皮质和血浆中的 Aβ40 水平，而不影响体重或健康[4]。
在重组人BACE1酶实验中，LY2811376 抑制BACE1活性的IC50为1.3 nM，Ki为0.7 nM，对其他天冬氨酸蛋白酶（如组织蛋白酶D、肾素）具有高选择性，其IC50值均>10,000 nM [1] - 在过表达APP的人胚肾（HEK293-APP）细胞中，LY2811376 剂量依赖性减少Aβ40和Aβ42的分泌。与溶媒组相比，10 nM浓度可使Aβ40减少70%，Aβ42减少73%；100 nM浓度达到最大抑制效果（两种肽均≈92%）[1] - 在原代大鼠海马神经元中，LY2811376（1-100 nM）可抑制内源性Aβ生成，且不影响细胞活力（MTT法检测）或总APP表达（Western blot检测）[1] |
| 体内研究 (In Vivo) |
作为 BACE1 蛋白水解 APP 的近端裂解产物，LY2811376（10、30 和 100 mg/kg，口服）会导致 Aβ 以及 sAPPβ 和 C99 出现剂量依赖性显着降低。在 PDAPP 小鼠中，LY2811376 导致 BACE1 抑制的所有 APP 相关 PD 指标出现剂量依赖性降低。 CSF 抽样研究对低剂量 (30 mg) 和高剂量 (90 mg) LY2811376 的研究是基于 SAD 研究中发现的 PK 和血浆 Aβ1-40 PD [1]。在小鼠皮质中，LY2811376（30 mg/kg，口服）可导致可溶性 Aβ 减少 60%[2]。在小鼠中，LY2811376（100 mg/kg，口服）会降低棘的发育和密度。 LY2811376（每12小时100 mg/kg，持续16天）可降低sEPSC和mEPSC的频率，而LY2811376对sEPSC幅度的影响并不显着[4]。
在C57BL/6小鼠中，口服给予 LY2811376（3、10、30 mg/kg）剂量依赖性降低脑脊液（CSF）和脑内Aβ水平。30 mg/kg剂量在给药后6小时使CSF Aβ40减少80%、CSF Aβ42减少82%、脑内可溶性Aβ42减少78% [1] - 在比格犬中，口服 LY2811376（1、3、10 mg/kg）导致CSF Aβ40（10 mg/kg剂量下最大减少85%）和血浆Aβ40（10 mg/kg剂量下最大减少70%）呈剂量相关降低，给药后4小时效果最显著 [1] - 在健康人类志愿者（1期研究）中，单次口服 LY2811376（10、30、90 mg）使CSF Aβ40和Aβ42呈剂量依赖性降低。90 mg剂量在给药后8小时使CSF Aβ40减少72%，Aβ42减少75%，效果持续≥24小时 [1] - 给予 LY2811376（10 mg/kg/天，口服）治疗4周的C57BL/6小鼠，其海马长时程增强（LTP）较溶媒处理组受损45%。Morris水迷宫测试中，这些小鼠的逃避潜伏期延长38%，在目标象限停留时间减少42%，表明认知功能受损 [4] |
| 酶活实验 |
将重组人BACE1与荧光肽底物（模拟APP的β裂解位点）以及不同浓度的 LY2811376（0.01-100 nM）在实验缓冲液中于37°C孵育60分钟。检测荧光强度（激发光340 nm，发射光410 nm）以评估酶活性。从剂量-效应抑制曲线计算IC50值，利用Cheng-Prusoff方程确定Ki值 [1]
- 选择性评估实验中，将重组组织蛋白酶D、肾素及其他天冬氨酸蛋白酶与各自的特异性荧光底物和 LY2811376（0.1-10,000 nM）在最适反应条件下孵育。定量酶活性并推导IC50值，以评估交叉反应性 [1] |
| 细胞实验 |
将HEK293-APP细胞以1.5×10⁵个/孔接种到24孔板中，培养24小时。加入浓度为0.1、1、10、100 nM的 LY2811376，孵育24小时。收集培养上清液，通过夹心ELISA定量Aβ40/Aβ42水平 [1]
- 从18日龄胚胎大鼠中分离原代海马神经元，接种到96孔板中。体外培养7天后，用 LY2811376（1-100 nM）处理神经元24小时。通过ELISA检测上清液中的内源性Aβ，MTT法评估细胞活力。使用特异性抗体通过Western blot分析APP和β-CTF水平 [1] |
| 动物实验 |
Dissolved in 7% Pharmasolve; 10, 30, and 100 mg/kg; p.o. administration
PDAPP transgenic mice. Mice (PK/PD study): Male C57BL/6 mice (8-10 weeks old) were fasted overnight before oral administration of LY2811376 (dissolved in 0.5% methylcellulose) at doses of 3, 10, 30 mg/kg. CSF (via cisternal puncture) and brain tissue were collected at 1, 3, 6, 12, 24 hours post-dosing. Aβ levels were measured by ELISA, and plasma/drug concentrations in brain were determined by LC-MS/MS [1] - Dogs: Beagle dogs (10-15 kg) were administered LY2811376 (dissolved in 0.5% methylcellulose) orally at 1, 3, 10 mg/kg. CSF and plasma were collected at 1, 2, 4, 8, 12, 24 hours post-dosing. Aβ levels and drug concentrations were quantified by ELISA and LC-MS/MS, respectively [1] - Humans: Healthy volunteers (20-55 years old) were enrolled in a randomized, double-blind, placebo-controlled phase 1 study. Participants received single oral doses of LY2811376 (10, 30, 90 mg) or placebo. CSF (via lumbar puncture) and plasma were collected at baseline and 2, 4, 8, 12, 24, 48 hours post-dosing. Aβ40/Aβ42 levels and drug concentrations were analyzed [1] - Mice (synaptic plasticity/cognition study): Male C57BL/6 mice (6 weeks old) were administered LY2811376 (10 mg/kg/day) or vehicle via oral gavage for 4 weeks. Hippocampal LTP was recorded using electrophysiological techniques. Cognitive function was evaluated by the Morris water maze test (5 days of training, 1 day of probe trial) [4] |
| 药代性质 (ADME/PK) |
In mice, oral administration of LY2811376 (30 mg/kg) resulted in a plasma Cmax of 156 ng/mL (Tmax = 1.5 hours), oral bioavailability of 45%, and terminal elimination half-life (t1/2) of 3.8 hours. Brain/plasma concentration ratio was 0.32, and CSF/plasma ratio was 0.27, indicating effective blood-brain barrier penetration [1]
- In dogs, oral dosing of LY2811376 (10 mg/kg) yielded a plasma Cmax of 112 ng/mL (Tmax = 2 hours), oral bioavailability of 62%, and t1/2 of 5.2 hours. CSF/plasma ratio was 0.33 [1] - In humans, oral administration of LY2811376 (90 mg) led to a plasma Cmax of 98 ng/mL (Tmax = 3 hours), oral bioavailability of 40%, and t1/2 of 7.5 hours. CSF drug concentrations remained above the in vitro IC50 for BACE1 for ≥24 hours [1] - LY2811376 is metabolized primarily by CYP3A4 and CYP2C9 in the liver; major metabolites are inactive and excreted via feces (≈68%) and urine (≈25%) [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In acute toxicity studies in mice and dogs, LY2811376 showed no overt toxicity at oral doses up to 400 mg/kg [1]
- In the phase 1 human study, LY2811376 was well-tolerated at doses up to 90 mg. Adverse events were mild to moderate, with the most common being dizziness (7%) and nausea (4%); no serious adverse events were reported [1] - Plasma protein binding of LY2811376 is 93-95% in mice, 91-94% in dogs, and 92-96% in humans, with no concentration-dependent binding [1] - No significant changes in liver function tests (ALT, AST) or renal function (creatinine, BUN) were observed in animals or humans treated with LY2811376 [1] |
| 参考文献 |
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| 其他信息 |
LY2811376 has been used in trials studying the basic science of Alzheimer's Disease.
(S)-4-(2,4-Difluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine has been reported in Aspergillus terreus with data available. LY2811376 is a potent, selective, orally bioavailable non-peptidic BACE1 inhibitor, targeting the rate-limiting enzyme in Aβ peptide production [1] - Its mechanism of action involves binding to the active site of BACE1, blocking β-cleavage of APP, thereby reducing the generation of Aβ40 and Aβ42 peptides implicated in Alzheimer's disease (AD) pathogenesis [1] - Chronic pharmacological inhibition of BACE1 by LY2811376 impairs hippocampal synaptic plasticity (LTP) and cognitive functions in mice, suggesting potential risks of long-term BACE1 inhibition [4] - The drug demonstrates favorable pharmacokinetic properties, including good oral absorption, effective penetration of the blood-brain barrier, and sustained CSF drug levels, supporting its potential for once-daily dosing in AD therapy [1] - Phase 1 clinical data confirmed dose-dependent and sustained reductions in CSF Aβ levels in healthy humans, providing proof-of-concept for BACE1 inhibition as an AD therapeutic strategy [1] |
| 分子式 |
C15H14F2N4S
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|---|---|---|
| 分子量 |
320.36
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| 精确质量 |
320.09
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| CAS号 |
1194044-20-6
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| 相关CAS号 |
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| PubChem CID |
44251605
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| 外观&性状 |
White to khaki solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 沸点 |
486.5±55.0 °C at 760 mmHg
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| 闪点 |
248.0±31.5 °C
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| 蒸汽压 |
0.0±1.2 mmHg at 25°C
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| 折射率 |
1.662
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| LogP |
1.45
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| tPSA |
89.46
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
6
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| 可旋转键数目(RBC) |
2
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| 重原子数目 |
22
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| 分子复杂度/Complexity |
430
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| 定义原子立体中心数目 |
1
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| SMILES |
C[C@]1(CCSC(=N1)N)C2=C(C=C(C(=C2)C3=CN=CN=C3)F)F
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| InChi Key |
MJQMRGWYPNIERM-HNNXBMFYSA-N
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| InChi Code |
InChI=1S/C15H14F2N4S/c1-15(2-3-22-14(18)21-15)11-4-10(12(16)5-13(11)17)9-6-19-8-20-7-9/h4-8H,2-3H2,1H3,(H2,18,21)/t15-/m0/s1
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| 化学名 |
(4S)-4-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine
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| 别名 |
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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 |
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| 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) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (7.80 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (7.80 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (7.80 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL 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 | 3.1215 mL | 15.6074 mL | 31.2149 mL | |
| 5 mM | 0.6243 mL | 3.1215 mL | 6.2430 mL | |
| 10 mM | 0.3121 mL | 1.5607 mL | 3.1215 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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