PLX5622 hemifumarate 是高度选择性的、能透过血脑屏障的、口服有效的CSF1R抑制剂,IC50值为 0.016 μM,Ki值为 5.9 nM,可用于病程发展前和过程中,扩大的和特异性的小胶质细胞的消除。PLX5622 hemifumarate 具有较好的药理学特性。
生物活性 | PLX5622 hemifumarate is a highly selective brain penetrant and orally activeCSF1Rinhibitor (IC50=0.016 μM;Ki=5.9 nM). PLX5622 hemifumarate allows for extended and specific microglial elimination, preceding and during pathology development. PLX5622 hemifumarate demonstrates desirable PK properties in variesanimals[1][2]. |
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体外研究 (In Vitro) | PLX5622 (1-20 μM; 3 days) hemifumarate effectively depletes microglia without affecting oligodendrocytes or astrocytes in cerebellar slices. PLX5622 (4 μM; 3 days) hemifumarate causes a 30-40% reduction in NG2+ or PDGFRα+ cells, and this increased to 90-95% at 20 μM. No reduction of NG2+ or PDGFRα+ OPCs is observed in slices exposed to 1 μM or 2 μM PLX5622 despite robust (~95%) depletion of the microglial cells[3].
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体内研究 (In Vivo) | Pharmacodynamics of PLX5622 hemifumarate in preclinical studies PLX5622 (1200 ppm; chow; for 3 weeks or 3 days; adult C57/Bl6 wild type mice) hemifumarate leads to around 80% of microglia lost after 3 days of treatment and a 99% microglia loss after 3 weeks of treatment. PLX5622 (adult C57/Bl6 wild type mice aged 3 months; diet for 3 weeks) decreases microglia in cortex, striatum, cerebellum and hippocampus[4]. PLX5622 (50 mg/kg; intraperitoneal injection; once (neonatal rat) or twice (adult rat) a day; for a total of 14 days) hemifumarate depletes microglia by 80-90% within 3 days of treatment, which increases to >90% by 7 days. After 14 days of PLX5622 treatment, microglia is depleted by >96% in both neonates and adults while preserving baseline astrocyte quantity. (A single daily injection of 0.65% PLX5622 suspended in 5% dimethyl sulfoxide and 20% Kolliphor RH40 in 0.01 M PBS is sufficient for neonatal microglia depletion, adult depletion requires injections twice daily)[5]. PLX5622 (formulated in AIN-76A standard chow at 1200 mg/kg; for 28 days) hemifumarate leads to reduction in microglia throughout the CNS in 14-month-old 5xfAD mice[6].
Pharmacokinetics of PLX5622 hemifumarate in preclinical species[4]
Species | IV | PO (gavage) | Dose (mg/kg) | AUC0-∞ (ngohr/mL) | CL (mL/min/kg) | Vss (L/kg) | t1/2 (hr) | Dose (mg/kg) | AUC0-∞ (ngohr/mL) | Cmax (ng/mL) | F | Mouse | 1.92 | 15,500 | 2.1 | 0.34 | 2.6 | 45 | 215,000 | 26,300 | 59% | Rat (male) | 1.13 | 2,630 | 7.7 | 1.2 | 2.3 | 45 | 99,600 | 12,000 | 95% | Rat (female) | 1.13 | 5,110 | 3.7 | 1.0 | 3.9 | 45 | 181,000 | 15,600 | 89% | Dog | 1.00 | 6,230 | 3.0 | 2.3 | 15 | 45 | 96,500 | 3,630 | 34% | Monkey | 1.35 | 2,100 | 11 | 1.6 | 2.2 | ND | ND | ND | ND |
Preparation of gavage dosing suspensions for PLX5622 hemifumarate[4] PLX5622 hemifumarate is dissolved in DMSO at a concentration that is 20x the final dosing solution. The compound stock is protected from light. A fresh stock is made each week. The components of the diluent generally are prepared a day or more in advance because they take time to dissolve completely: a) 2% hydroxypropyl methyl cellulose (HPMC): 2.0 g powder was brought to 100 mL deionized water; b) 25% Polysorbate 80 (PS80): 25 g was brought to 100 mL deionized water. To make 100 mL diluent, add 25 mL of 2% HPMC stock (0.5% final) and 4 mL of 25% PS80 stock (1% final) to 71 mL deionized water to have final 100 mL. Final composition after mixing with compound: 0.5% HPMC, 1% PS80, 5% DMSO. On each dosing day, the compound stock is diluted 20-fold as follows: 19 volumes of diluent are measured into the tube, and 1 volume of the 20x compound/DMSO stock is added. The cap is closed and the content of the tube is mixed by inversion and placed in a sonicating water bath to make a uniform suspension.
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | 4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
溶解性数据 | In Vitro: DMSO : 100 mg/mL(220.53 mM;Need ultrasonic) 配制储备液 1 mM | 2.2053 mL | 11.0266 mL | 22.0531 mL | 5 mM | 0.4411 mL | 2.2053 mL | 4.4106 mL | 10 mM | 0.2205 mL | 1.1027 mL | 2.2053 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80℃, 6 months; -20℃, 1 month (sealed storage, away from moisture)。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液,再依次添加助溶剂: ——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用;
以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 3.25 mg/mL (7.17 mM); Clear solution
此方案可获得 ≥ 3.25 mg/mL (7.17 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 32.5 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂: 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 3.25 mg/mL (7.17 mM); Clear solution
此方案可获得 ≥ 3.25 mg/mL (7.17 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 32.5 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 3.25 mg/mL (7.17 mM); Clear solution
此方案可获得 ≥ 3.25 mg/mL (7.17 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例,取 100 μL 32.5 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。 *以上所有助溶剂都可在本网站选购。
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