| 产品介绍 |
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。
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| 生物活性 |
PLX5622 hemifumarate is a highly selective brain penetrant and orally active CSF1R inhibitor (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 varies animals.
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| 体外研究 |
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.
西域 has not independently confirmed the accuracy of these methods. They are for reference only. |
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| 体内研究 |
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-∞
(ng•hr/mL) |
CL
(mL/min/kg) |
Vss
(L/kg) |
t1/2
(hr) |
Dose
(mg/kg) |
AUC0-∞
(ng•hr/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.
西域 has not independently confirmed the accuracy of these methods. They are for reference only. |
|---|
| 体内研究 |
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-∞
(ng•hr/mL) |
CL
(mL/min/kg) |
Vss
(L/kg) |
t1/2
(hr) |
Dose
(mg/kg) |
AUC0-∞
(ng•hr/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.
西域 has not independently confirmed the accuracy of these methods. They are for reference only. |
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| 性状 | Solid |
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| 溶解性数据 |
In Vitro:
DMSO : 100 mg/mL (220.53 mM; Need ultrasonic)
配制储备液
|
浓度
溶剂体积
质量
|
1 mg |
5 mg |
10 mg |
| 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°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)。-80°C 储存时，请在 6 个月内使用，-20°C 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
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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-CD in 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 μL 20% 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 西域 网站选购。
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| 运输条件 |
Room temperature in continental US; may vary elsewhere.
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| 储存方式 |
4°C, sealed storage, away from moisture
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| 参考文献 |
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. Spangenberg E, et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nat Commun. 2019 Aug 21;10(1):3758.
[Content Brief]
. Lee S, et al. Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain. Mol Pain. 2018 Jan-Dec;14:1744806918764979.
[Content Brief]
. Liu Y, et al. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 2019;318:32-41.
[Content Brief]
[4]. Badimon A, et al. Negative feedback control of neuronal activity by microglia. Nature. 2020;586(7829):417-423.
[Content Brief]
[5]. Andrew J. Riquier, et al. Astrocytic response to neural injury is larger during development than in adulthood and is not predicated upon the presence of microglia, Brain, Behavior, & Immunity-Health, Volume 1, 2020, 100010, ISSN 2666-3546.
[6]. Spangenberg EE, et al. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016;139(Pt 4):1265-1281.
[Content Brief]
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