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PLX5622

MCE China：PLX5622

Brand：MedChemExpress (MCE)

Cat. No.HY-114153

CAS：1303420-67-8

Purity：99.72%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month

Shipping：Room temperature in continental US; may vary elsewhere.

Description：PLX5622 is a highly selective brain penetrant and orally active CSF1R inhibitor (IC50=0.016 μM; Ki=5.9 nM). PLX5622 allows for extended and specific microglial cells elimination, preceding and during pathology development. PLX5622 demonstrates desirable PK properties in varies animals.

In Vitro：PLX5622 (1-20 μM; 3 days) effectively depletes microglia without affecting oligodendrocytes or astrocytes in cerebellar slices. PLX5622 (4 μM; 3 days) 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].

In Vivo：Pharmacodynamics of PLX5622 in preclinical studies PLX5622 (1200 ppm; chow; for 3 weeks or 3 days; adult C57/Bl6 wild type mice) 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) 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) leads to reduction in microglia throughout the CNS in 14-month-old 5xfAD mice[6]. Pharmacokinetics of PLX5622 in preclinical species[1] 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[1] PLX5622 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.

IC50 & Target：IC50: 0.016 µM (CSF1R); Ki: 5.9 nM (CSF1R)[1][2] In Vitro PLX5622 (1-20 μM; 3 days) effectively depletes microglia without affecting oligodendrocytes or astrocytes in cerebellar slices. PLX5622 (4 μM; 3 days) 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]. MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. 0 --> PLX5622 Related Antibodies

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References：

[1]. 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]

[2]. 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]

[3]. 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]