MK-0952: Phosphodiesterase 4 (PDE4), with high selectivity for PDE4D (IC50 = 0.8 nM); IC50 values for other PDE4 subtypes: PDE4A = 3.2 nM, PDE4B = 2.5 nM, PDE4C = 4.1 nM; showed >1000-fold selectivity over other PDE families (PDE1-PDE3, PDE5-PDE11) [1]

1. MK-0952以浓度依赖性方式强效抑制重组人源PDE4酶活性，对PDE4D的亲和力最高（IC50=0.8 nM），且该抑制作用对底物cAMP具有竞争性[1]
2. 在原代大鼠皮质神经元中，MK-0952（1–100 nM）呈剂量依赖性升高细胞内cAMP水平（100 nM时达最大2.8倍升高），并通过蛋白质印迹法检测到cAMP反应元件结合蛋白（CREB）在Ser133位点的磷酸化水平上调（50 nM时升高1.9倍）[1]
3. 在人神经母细胞瘤SH-SY5Y细胞中，MK-0952（10 nM）处理24小时后，通过实时荧光定量PCR检测到脑源性神经营养因子（BDNF）mRNA表达升高2.2倍，通过酶联免疫吸附试验（ELISA）检测到BDNF蛋白水平升高1.7倍[1]
4. 在体外酶实验中，MK-0952在浓度高达10 μM时，未对胆碱酯酶（AChE/BuChE）活性表现出显著抑制作用[1]

给予 10 mg/kg MK-0952 的大鼠会感到疼痛 [1]。

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1. 在东莨菪碱诱导的记忆损伤成年C57BL/6小鼠模型中，口服给予MK-0952（0.1、0.3、1 mg/kg）可剂量依赖性改善新物体识别（NOR）实验表现：辨别指数从溶媒组的0.12提升至1 mg/kg剂量组的0.45，与未损伤的对照组小鼠水平相当[1]
2. 在存在年龄相关认知衰退的老年大鼠（20月龄）中，MK-0952（0.3、1、3 mg/kg，口服）显著增强莫里斯水迷宫（MWM）实验中的空间记忆：与溶媒处理的老年大鼠相比，1 mg/kg剂量组逃避潜伏期缩短35%，3 mg/kg剂量组缩短42%；探针实验中平台穿越次数在3 mg/kg剂量组增加2.1倍[1]
3. 在慢性脑低灌注诱导的大鼠轻度认知障碍（MCI）模型中，MK-0952（1 mg/kg，口服，每日1次，连续28天）逆转了被动回避记忆缺陷：步穿潜伏期从溶媒组的45秒延长至药物处理组的180秒，且海马区降低的p-CREB水平恢复至正常水平（较溶媒组升高1.8倍）[1]
4. MK-0952（0.1–3 mg/kg，口服）在雪貂（对PDE4抑制剂诱导的胃肠道毒性敏感的物种）中未诱发呕吐或腹泻（非选择性PDE4抑制剂的常见副作用）[1]

1. PDE4酶活性实验：纯化重组人源PDE4亚型（PDE4A-D），与不同浓度的MK-0952共同孵育在含[3H]-cAMP底物的反应缓冲液中。加入酶启动反应，30℃孵育30分钟后，100℃加热2分钟终止反应。利用阴离子交换树脂分离水解产物[3H]-5'-AMP与未水解的[3H]-cAMP，通过液体闪烁计数检测放射性，计算抑制率及IC50值[1]
2. PDE家族选择性实验：将MK-0952以1 μM浓度在包含11种PDE家族（PDE1-PDE11）的面板中进行测试，采用上述放射性检测法，通过计算酶抑制百分比确定相对于PDE4D的选择性比率[1]
3. 胆碱酯酶活性实验：将人重组乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）与MK-0952（0.1 nM–10 μM）及生色底物乙酰硫代胆碱/丁酰硫代胆碱共同孵育，通过412 nm处吸光度检测底物水解速率，从剂量-反应曲线计算抑制常数[1]

1. 大鼠皮质神经元中cAMP和p-CREB检测实验：从胚胎第18天的大鼠胎鼠中分离原代皮质神经元，在神经基础培养基中培养14天。神经元经MK-0952（1–100 nM）预处理1小时后，加入福斯高林（10 μM）升高cAMP水平。提取细胞内cAMP并通过竞争性ELISA定量。对于p-CREB分析，药物处理后裂解神经元，蛋白提取物经蛋白质印迹法检测总CREB和p-CREB（Ser133），通过光密度法对条带强度定量并以GAPDH为内参进行归一化[1]
2. SH-SY5Y细胞中BDNF表达实验：将SH-SY5Y细胞接种于6孔板，经维甲酸诱导分化7天。细胞经MK-0952（1–100 nM）处理24小时后，提取总RNA用于BDNF mRNA的qPCR分析（以GAPDH为参考基因）。蛋白分析则收集细胞上清液，通过夹心ELISA检测BDNF水平[1]

1. For mouse scopolamine-induced memory impairment model: Male C57BL/6 mice (8–10 weeks old) were pretreated with scopolamine (1 mg/kg, i.p.) 30 minutes before the training phase of the novel object recognition (NOR) test. MK-0952 was formulated in a vehicle of 10% hydroxypropyl-β-cyclodextrin in saline and administered orally by gavage at doses of 0.1, 0.3, 1 mg/kg 1 hour before scopolamine injection. The NOR test was performed 24 hours after training, with the discrimination index calculated as the ratio of time spent exploring the novel object to total exploration time [1]
2. For aged rat Morris water maze (MWM) test: Male Sprague-Dawley rats (20 months old) were given MK-0952 (0.3, 1, 3 mg/kg, p.o.) or vehicle once daily for 14 days. MWM training was conducted for 5 consecutive days (4 trials per day), with the escape latency to find a hidden platform recorded. A probe trial (without the platform) was performed on day 6 to assess spatial memory, measuring the number of crossings over the former platform location and time spent in the target quadrant [1]
3. For rat chronic cerebral hypoperfusion MCI model: Male Wistar rats (3 months old) underwent bilateral common carotid artery stenosis (BCAS) to induce chronic hypoperfusion. Four weeks post-surgery, rats with confirmed cognitive impairment received MK-0952 (1 mg/kg, p.o.) or vehicle once daily for 28 days. Passive avoidance memory was tested by measuring step-through latency in a shuttle box before and after treatment. Hippocampal tissue was dissected post-test, and p-CREB levels were analyzed by Western blot [1]
4. For ferret toxicity assessment: Male ferrets (1–2 years old) were administered MK-0952 (0.1, 0.3, 1, 3 mg/kg, p.o.) once daily for 7 days. The number of emetic episodes and diarrhea events was recorded every 2 hours for 8 hours post-dosing each day; body weight and food intake were also monitored throughout the study [1]

1. Absorption: After a single oral dose of 1 mg/kg, MK-0952 showed high oral bioavailability in rats (82%) and dogs (75%); peak plasma concentration (Cmax) was reached at 0.8 hours (rat) and 1.2 hours (dog), respectively [1]
2. Distribution: MK-0952 has excellent brain permeability. After oral administration (1 mg/kg), the brain/plasma ratio in rats was 1.5 and in mice it was 1.8; the concentration of the drug in the hippocampus and cortical regions (brain regions associated with memory) was 2.1 times higher than that in plasma [1]
3. Metabolism: MK-0952 is mainly metabolized in the liver by CYP3A4 and CYP2D6; the main metabolites include N-dealkylated and hydroxylated products, which are inactive against PDE4 [1]
4. Elimination: After oral administration, the terminal half-life (t1/2) of MK-0952 in rats was 3.5 hours and in dogs it was 5.2 hours; approximately 22% of the administered dose was excreted by the kidneys and approximately 68% by the feces in rats[1]. 5. Pharmacokinetic parameters (rat, 1 mg/kg orally): Cmax = 25 nM, Tmax = 0.8 hours, AUC0-∞ = 120 nM·h[1].

1. Plasma protein binding: MK-0952 has moderate plasma protein binding in humans (78%), rats (75%) and dogs (81%) [1]
2. Acute toxicity: In single-dose toxicity studies in mice and rats, MK-0952 was well tolerated at oral doses up to 300 mg/kg, with no deaths or significant weight loss observed; the LD50 in mice was >500 mg/kg (oral) [1]
3. Repeat-dose toxicity: In a 28-day repeat-dose study in rats (oral once daily at doses of 0.3, 1, 3, and 10 mg/kg), MK-0952 did not cause histopathological changes in the liver, kidneys, brain, or gastrointestinal tract at doses ≤3 mg/kg; the No Adverse Effect Level (NOAEL) was 3 mg/kg/day [1]
4. Gastrointestinal toxicity: Unlike non-selective PDE4 inhibitors (e.g., rolipram), MK-0952 showed moderate plasma protein binding at doses up to 3 mg/kg. At a dose of mg/kg (orally), no vomiting or diarrhea was caused in ferrets, and this dose significantly enhanced cognitive function in rodent models [1]. 5. Drug interactions: In human liver microsomes, MK-0952 did not inhibit or induce major CYP450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at therapeutic concentrations (≤100 nM) [1].

[1]. Discovery of MK-0952, a Selective PDE4 Inhibitor for the Treatment of Long-Term Memory Loss and Mild Cognitive Impairment. Epub 2010 Sep 21.

[2]. Dual Functional Cholinesterase and PDE4D Inhibitors for the Treatment of Alzheimer's Disease: Design, Synthesis and Evaluation of tacrine-pyrazolo[3,4-b]pyridine Hybrids. Behav Brain Res. 2016 Apr 15;303:26-33.

1. MK-0952 is a novel selective PDE4D inhibitor for the treatment of long-term memory loss and mild cognitive impairment (MCI) with fewer gastrointestinal side effects compared to non-selective PDE4 inhibitors [1]. 2. The mechanism of action of this drug is to inhibit PDE4D-mediated cAMP hydrolysis, thereby increasing intracellular cAMP levels, activating the CREB signaling pathway, and upregulating neurotrophic factors (e.g., BDNF) in the hippocampus and cortex (key areas for learning and memory) [1]. 3. MK-0952 was tested in a phase I clinical trial in healthy volunteers, and the results showed that it had good safety, tolerability, and central nervous system penetration [1]. 4. Literature [2] mainly focuses on tacrine-pyrazolo[3,4-b]pyridine hybrid as a dual cholinesterase/PDE4D inhibitor for the treatment of Alzheimer's disease, but does not mention MK-0952 [2].

C28H21N3O4F-.NA+

505.47224

483.159

934995-87-6

934995-87-6 (acid);934995-88-7 (sodium);

11755033

White to off-white solid powder

4.846

104.78

2

7

6

36

936

2

C1CC1NC(=O)C2=CN(C3=C(C2=O)C=CC=N3)C4=CC=CC(=C4)C5=CC(=C(C=C5)[C@@H]6C[C@H]6C(=O)O)F

PSYPBAHXIIVDCJ-FCHUYYIVSA-N

InChI=1S/C28H22FN3O4/c29-24-12-16(6-9-19(24)21-13-22(21)28(35)36)15-3-1-4-18(11-15)32-14-23(27(34)31-17-7-8-17)25(33)20-5-2-10-30-

(1R,2R)-2-(3'-(3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1(4H)-yl)-3-fluoro-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

MK0952; MK 0952; MK-0952

2934.99.9001

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/受潮和光照。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~103.41 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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;
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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。