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| 靶点 |
LY2886721 specifically targets β-site amyloid precursor protein cleaving enzyme 1 (BACE1) (Ki = 0.4 nM; IC50 = 0.9 nM) [1]
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| 体外研究 (In Vitro) |
当 HEK293Swe 细胞暴露于浓度不断增加的 LY2886721 过夜时，释放到条件培养基中的 Aβ 量以浓度依赖性方式减少。 BACE 抑制机制得到了几乎相似的 Aβ1-42 和 Aβ1-40 抑制 EC50 分别为 18.5 和 19.7 nM 的支持[1]。当 PDAPP 神经元细胞在过夜暴露过程中暴露于浓度不断增加的 LY2886721 时，Aβ 的合成会呈浓度依赖性减少。 PDAPP 神经元培养物中 Aβ1-40 和 Aβ1-42 抑制的 EC50 与 HEK293Swe 细胞中的类似，值约为 10 nM[1]。
在重组人BACE1酶实验中，LY2886721 抑制BACE1活性的IC50为0.9 nM，Ki为0.4 nM，表现出高 potency和选择性。它对其他天冬氨酸蛋白酶（如组织蛋白酶D、肾素）的抑制作用可忽略不计，IC50值均>10,000 nM [1] - 在过表达APP的人神经母细胞瘤（SH-SY5Y-APP）细胞中，LY2886721 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68%，Aβ42减少72%；100 nM浓度达到最大抑制效果（两种肽均≈90%）[1] - 在原代大鼠皮质神经元中，LY2886721（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APP表达（Western blot检测）[1] |
| 体内研究 (In Vivo) |
用 LY2886721（3-30 mg/kg；口服剂量；PDAPP 小鼠）治疗可显着降低皮质和海马区域的 Aβ1-x 水平。 LY2886721 治疗导致脑实质中 C99 和 sAPPβ 水平显着降低[1]。
在C57BL/6小鼠中，口服给予 LY2886721（1、3、10 mg/kg）剂量依赖性降低脑脊液（CSF）中Aβ40和Aβ42水平。10 mg/kg剂量在给药后6小时使CSF Aβ40减少75%，Aβ42减少78% [1] - 在比格犬中，口服 LY2886721（0.3、1、3 mg/kg）导致CSF Aβ40（3 mg/kg剂量下最大减少82%）和血浆Aβ40（3 mg/kg剂量下最大减少65%）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 LY2886721（5、15、50 mg）使CSF Aβ40和Aβ42呈剂量依赖性降低。50 mg剂量在给药后8小时使CSF Aβ40减少64%，Aβ42减少68%，效果持续≥24小时 [1] |
| 酶活实验 |
将重组人BACE1与荧光肽底物（对应APP的β裂解位点）以及不同浓度的 LY2886721（0.01-100 nM）在 assay 缓冲液中于37°C孵育60分钟。检测荧光强度（激发光320 nm，发射光405 nm）以评估酶活性。从剂量-效应抑制曲线计算IC50值，利用Cheng-Prusoff方程推导Ki值 [1]
- 选择性实验中，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荧光底物和 LY2886721（0.1-10,000 nM）在最适反应条件下孵育。定量酶活性并测定IC50值，以评估选择性 [1] |
| 细胞实验 |
将SH-SY5Y-APP细胞以2×10⁵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 LY2886721，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皮质神经元，接种到96孔板中。培养7天后，用 LY2886721（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（β羧基末端片段）水平 [1] |
| 动物实验 |
Animal/Disease Models: Female hemizygous APPV717F transgenic mice (PDAPP) (2-3 months old)[1]
Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg Route of Administration: Oral administration Experimental Results: Hippocampal and cortical levels of Aβ1-x were Dramatically decreased . Mice: Male C57BL/6 mice (8-10 weeks old) were fasted overnight before oral administration of LY2886721 (dissolved in 0.5% methylcellulose) at doses of 1, 3, 10 mg/kg. CSF and plasma were collected at 1, 3, 6, 12, 24 hours post-dosing. Aβ40/Aβ42 levels were measured by ELISA, and plasma drug concentrations were determined by LC-MS/MS [1] - Dogs: Beagle dogs (12-18 kg) were administered LY2886721 (dissolved in 0.5% methylcellulose) orally at 0.3, 1, 3 mg/kg. CSF (via cisternal puncture) 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 (18-55 years old) were enrolled in a single-center, randomized, double-blind, placebo-controlled phase 1 study. Participants received single oral doses of LY2886721 (5, 15, 50 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] |
| 药代性质 (ADME/PK) |
In mice, oral administration of LY2886721 (10 mg/kg) resulted in a plasma Cmax of 123 ng/mL (Tmax = 1 hour), oral bioavailability of 42%, and terminal elimination half-life (t1/2) of 3.2 hours. CSF/plasma concentration ratio was 0.25, indicating effective blood-brain barrier penetration [1]
- In dogs, oral dosing of LY2886721 (3 mg/kg) yielded a plasma Cmax of 98 ng/mL (Tmax = 2 hours), oral bioavailability of 58%, and t1/2 of 4.5 hours. CSF/plasma ratio was 0.31 [1] - In humans, oral administration of LY2886721 (50 mg) led to a plasma Cmax of 86 ng/mL (Tmax = 3 hours), oral bioavailability of 38%, and t1/2 of 6.8 hours. CSF/plasma ratio was 0.28, with CSF drug concentrations maintained above the in vitro IC50 for BACE1 for ≥24 hours [1] - LY2886721 is metabolized primarily by CYP3A4 in the liver; major metabolites are inactive and excreted primarily in feces (≈65%) and urine (≈28%) [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In acute toxicity studies in mice and dogs, LY2886721 showed no overt toxicity at doses up to 300 mg/kg (oral) [1]
- In the phase 1 human study, LY2886721 was well-tolerated at doses up to 50 mg. Adverse events were mild to moderate, with the most common being headache (8%) and fatigue (5%), no serious adverse events were reported [1] - Plasma protein binding of LY2886721 is 92-94% in mice, 90-93% in dogs, and 91-95% 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 LY2886721 [1] |
| 参考文献 | |
| 其他信息 |
LY2886721 has been used in trials studying the basic science of Alzheimer's Disease.
LY2886721 is a potent, selective, orally bioavailable small-molecule inhibitor of BACE1, a key enzyme in the amyloidogenic pathway of APP processing [1] - Its mechanism of action involves binding to the active site of BACE1, inhibiting β-cleavage of APP, thereby reducing the production of Aβ peptides (Aβ40 and Aβ42) that are implicated in Alzheimer's disease pathogenesis [1] - The drug exhibits favorable pharmacokinetic properties, including good oral absorption, effective blood-brain barrier penetration, and a prolonged duration of action, supporting its potential for once-daily dosing [1] - The phase 1 study demonstrated dose-dependent and sustained reductions in CSF Aβ levels in healthy humans, providing proof-of-concept for BACE1 inhibition as a therapeutic strategy for Alzheimer's disease [1] |
| 分子式 |
C18H16F2N4O2S
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|---|---|---|
| 分子量 |
390.41
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| 精确质量 |
390.096
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| CAS号 |
1262036-50-9
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| 相关CAS号 |
1262036-49-6
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| PubChem CID |
49837968
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.6±0.1 g/cm3
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| 折射率 |
1.706
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| LogP |
0.8
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| tPSA |
112.4
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
7
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| 可旋转键数目(RBC) |
3
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| 重原子数目 |
27
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| 分子复杂度/Complexity |
610
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| 定义原子立体中心数目 |
2
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| SMILES |
C1[C@H]2CSC(=N[C@]2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N
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| InChi Key |
NIDRNVHMMDAAIK-YPMLDQLKSA-N
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| InChi Code |
InChI=1S/C18H16F2N4O2S/c19-11-1-4-15(22-6-11)16(25)23-12-2-3-14(20)13(5-12)18-9-26-7-10(18)8-27-17(21)24-18/h1-6,10H,7-9H2,(H2,21,24)(H,23,25)/t10-,18-/m0/s1
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| 化学名 |
N-(3-((4aS,7aS)-2-amino-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide
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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 mg/mL (5.12 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。
例如，若需制备1 mL的工作液，可将100 μL 20.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。 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 | 2.5614 mL | 12.8070 mL | 25.6141 mL | |
| 5 mM | 0.5123 mL | 2.5614 mL | 5.1228 mL | |
| 10 mM | 0.2561 mL | 1.2807 mL | 2.5614 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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