ChemicalBook Product Catalog Biochemical Engineering Inhibitors Angiogenesis FLT3 inhibitors PLX5622

PLX5622

Product NamePLX5622
CAS1303420-67-8
MFC21H19F2N5O
MW395.41
EINECS
MOL File1303420-67-8.mol

Chemical Properties

Density	1.364±0.06 g/cm3(Predicted)
storage temp.	-20°C
solubility	Soluble in DMSO (>25 mg/ml)
form	solid
pka	13+-.0.40(Predicted)
color	Pale yellow
Stability	Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChI	InChI=1S/C21H19F2N5O/c1-12-5-17-14(9-26-20(17)25-8-12)6-13-3-4-18(28-19(13)23)24-10-15-7-16(22)11-27-21(15)29-2/h3-5,7-9,11H,6,10H2,1-2H3,(H,24,28)(H,25,26)
InChIKey	NSMOZFXKTHCPTQ-UHFFFAOYSA-N
SMILES	C1(OC)=NC=C(F)C=C1CNC1=NC(F)=C(CC2C3=CC(C)=CN=C3NC=2)C=C1

Usage And Synthesis

Description

PLX5622 (1303420-67-8) is a highly selective (>20 fold over KIT and FLT3, >60 fold over 200 other kinases) and brain-penetrant inhibitor of colony-stimulating factor 1 receptor (CSF1R; IC50 = 16 nM).1 It prevented plaque formation in 5xFAD1 and 3xTg2 mouse models of Alzheimer’s disease via elimination of microglia in a CSF1R-dependent manner. PLX5622 showed efficacy in a mouse neuropathic pain model via reduction of CD86+ macrophages resulting in reduced expression of pro-inflammatory cytokines.3 It also was able to ameliorate peripheral neuropathy in aging mice.4 PLX5622 displayed neuroprotective effects during the chronic phase of a traumatic brain injury mouse model.5 PLX5622 has also been shown to affect myeloid and lymphoid compartments, indicating that its affects are not limited to microglia and include peripheral immune cells.6

Uses

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[1][2].

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)	AUC_0-∞ (ng hr/mL)	CL (mL/min/kg)	Vss (L/kg)	t_1/2 (hr)	Dose (mg/kg)	AUC_0-∞ (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.

References

[1] ELIZABETH SPANGENBERG. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model.[J]. ACS Combinatorial Science, 2019: 3758. DOI:10.1038/s41467-019-11674-z
[2] NABIL N DAGHER. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice.[J]. Journal of Neuroinflammation, 2015: 139. DOI:10.1186/s12974-015-0366-9
[3] SEUNGHWAN LEE. Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain.[J]. Molecular Pain, 2018, 14: 1744806918764979. DOI:10.1177/1744806918764979
[4] XIDI YUAN. Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.[J]. Journal of Neuroscience, 2018, 38 19: 4610-4620. DOI:10.1523/jneurosci.3030-17.2018
[5] REBECCA J HENRY. Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.[J]. Journal of Neuroscience, 2020: 2960-2974. DOI:10.1523/jneurosci.2402-19.2020
[6] FENGYANG LEI. CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020: 23336-23338. DOI:10.1073/pnas.1922788117

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