| Identification | Back Directory | [Name]
PLX5622 | [CAS]
1303420-67-8 | [Synonyms]
PLX5622
PLX 5622;PLX-5622
PLX5622 USP/EP/BP
5-Fluoro-N-[6-fluoro-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-2-methoxy-3-pyridinemethanamine
3-Pyridinemethanamine, 5-fluoro-N-[6-fluoro-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-2-methoxy- | [Molecular Formula]
C21H19F2N5O | [MDL Number]
MFCD32201039 | [MOL File]
1303420-67-8.mol | [Molecular Weight]
395.41 |
| Chemical Properties | Back Directory | [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 |
| Hazard Information | Back Directory | [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) | 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.
| [storage]
Store at -20°C | [References]
Spangenberg et al. (2019) Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model; Nat. Commun.?10 3758
Dagher et al. (2015) Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice; J.? Neuroinflammation 12 139
Lee et al. (2018) Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain; Mol.? Pain?14 1
Yaun et al. (2018) Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.; J.? Neurosci.?38 4610
Henry et al. (2020) Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.; J.? Neurosci.?40 2960
Lei et al. (2020) CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages.; Proc. ?Natl. Acad. Sci USA?117 23336 |
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