PLX5622 hemifumarate

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PLX5622 hemifumarate

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MCE 国际站：PLX5622 hemifumarate

产品活性：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，K_i 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。

研究领域：Protein Tyrosine Kinase/RTK

作用靶点：c-Fms

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.

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.
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).
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.

Pharmacokinetics of PLX5622 hemifumarate in preclinical species

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
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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