1029044-16-3

Basic information

• Product Name: PLX3397 (Pexidartinib)
• Synonyms: PLX-3397;Pexidartinib (PLX3397);Pexidartinib;3-Pyridinemethanamine,N-[5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-;N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine;5-((5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl);PLX3397 (Pexidartinib);PLX339
• CAS NO: 1029044-16-3
• Molecular Formula: C₂₀H₁₅ClF₃N₅
• Molecular Weight: 417.82
• EINECS: -0
• Product Categories: Inhibitors
• Mol File: 1029044-16-3.mol
• Article Data: 7

Chemical Properties

• Appearance: /
• Density: 1.458±0.06 g/cm3(Predicted)
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to at least 10 mg/ml)
• PKA: 12.81±0.40(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: PLX3397 (Pexidartinib)(CAS DataBase Reference)
• NIST Chemistry Reference: PLX3397 (Pexidartinib)(1029044-16-3)
• EPA Substance Registry System: PLX3397 (Pexidartinib)(1029044-16-3)

Safety Data

• Hazardous Substances Data: 1029044-16-3(Hazardous Substances Data)

Usage

Description

PLX3397 (Pexidartinib) is a novel, orally available small molecule tyrosine kinase inhibitor (TKI) with potent and selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). It has been developed by Daiichi Sankyo for the treatment of tenosynovial giant cell tumor (TGCT) and has the ability to cross the blood-brain barrier.
Used in Pharmaceutical Industry:
PLX3397 (Pexidartinib) is used as a tyrosine kinase inhibitor for the treatment of tenosynovial giant cell tumor (TGCT) and as a potential therapeutic agent for other cancer types.
Used in Oncology Research:
PLX3397 (Pexidartinib) is used as a research tool for studying the inhibition of colony stimulating factor-1 receptor (CSF1R), KIT, and FLT3-ITD in various cancer models, including mammary tumor-bearing mice and glioblastoma multiforme mouse models.
Used in Drug Development:
PLX3397 (Pexidartinib) is used as a multi-targeted receptor tyrosine kinase (RTK) inhibitor for the development of new cancer therapies, particularly for targeting the CSF1R, Kit, and Flt3 pathways.
Used in Combination Therapy:
PLX3397 (Pexidartinib) is used in combination with other drugs, such as paclitaxel, to enhance the antitumor efficacy by blocking macrophage recruitment and microglial stimulation in various cancer models.

Synthetic Routes

The synthetic routes of pexidartinib were developed by Daiichi Sankyo Company6. A novel efficient synthetic route for pexidartinib was designed via Tsuji–Trost/Heck tandem reaction in combination with palladium and silver catalysis, which avoids the need for ultra-low temperature and greatly reduces the amount of corrosive trifluoroacetic acid. The cheap and easily available materials and reagents and easy operations for workup and purification make this route more practical.

Anti-tumor Activity

Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

in vitro

plx3397 strongly dampened the systemic and local accumulation of macrophages driven by b16f10 melanomas, without affecting gr-1+ myeloid derived suppressor cells [1].

in vivo

wild-type c57 mice were orthotopically injected with gl261 cells and fed with plx3397 compound. after 2 wks, tumors in the control group showed extensive microglia infiltration. in animals fed plx3397, however, there was a substantial reduction in the number of iba1- positive cells at the tumor [2].

References

1)?DeNardo?et al.?(2011)?Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy;?Cancer Discov.?1?54 2)?Mok?et al.?(2014)?Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy;?Cancer Res.74?15 3)Sluijter?et al.?(2014)?Inhibition of CSF-1R supports T-cell mediated melanoma therapy;?PLoS One?9?e104230 4)?Peranzoni?et al.?(2018)?Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment;?Proc. Natl. Acad. Sci. USA?115?E4041 5)?Shi?et al.?(2019)?Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy;?Mol. Ther.?27?244 6) Dammeijer?et al.?(2017)?Depletion pf Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy;?Cancer Immunol. Res.?5?535

Upstream product

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• 2040295-05-2 C₂₃H₂₇ClN₄O₅ 
• 386704-12-7 6-(trifluoromethyl)pyridine-3-carbaldehyde 
• 387350-39-2 1-(6-(trifluoromethyl)pyridin-3-yl)methanamine 
• 823201-92-9 N-(3-bromo-5-chloro-pyridin-2-yl)-4'-methyl-benzenesulfonamide 
• 26163-03-1 2-amino-3-bromo-5-chloropyridine 
• 503039-05-2 5-bromo-N-(4-methoxybenzyl)pyridin-2-amine 
• 1072-97-5 5-bromo-2-pyridylamine 
• 159451-66-8 tert-butyl N-(5-bromopyridin-2-yl)carbamate 
• 108274-33-5 5-(bromomethyl)-2-(trifluoromethyl)pyridine 

Relevant articles and documents

Exploratory Process Development of Pexidartinib through the Tandem Tsuji-Trost Reaction and Heck Coupling

A novel synthetic route to CSF1R inhibitor pexidartinib was designed and demonstrated. Crucial to the successful synthesis is a tandem Tsuji-Trost reaction and Heck coupling in combination with palladium and silver catalysis. The final product was obtained via five steps in 49percent yield with purity as high as 99.2percent. The cheap and available materials and reagents and easy operations for workup and purification make this route more practical.

Synthetic method for continuously producing pexidartinib

The invention relates to the field of chemical synthesis, and particularly discloses a synthetic method for continuously producing pexidartinib. According to the method, 5-chloro-7-azaindole and 2-chloro-5-chloromethylpyridine are adopted as initial raw materials; an alkylation intermediate is obtained with a high yield through an alkylation reaction of the 5-chloro-7-azaindole, the intermediate does not need purification and directly and continuously participates a next-step reaction, and an amino substitution reaction on the intermediate and 3-aminomethyl-6-(trifluoromethyl) pyridine is performed to obtain a target product pexidartinib. The invention provides the synthetic route for two-step continuous production of the pexidartinib for the first time, the method is particularly suitablefor commercial mass production, and can be used for preparing the pexidartinib with low cost, high yield, high purity and high environmental protection property.

Simple preparation method of (by machine translation)

The invention relates to a simple preparation method, in particular to a simple preparation method of. The method utilizes N - (2 -trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 - alkoxymethylpyridine or N - (2 - trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 - cyanmethylpyridine (II) and acetonitrile in the presence of a base to give N - (2 -trifluoromethyl-pyridin -5 -yl) methyl -2 - amino -5 -cyanacetylmethylpyridine (III), compound III and nitromethane to prepare compound IV. The compound V, which is obtained by the addition, of 2 3 - dichloropropenal addition and base, is then subjected to hydrogenation reduction - cyclization in the presence of a catalyst to prepare the piroxicin. The method is cheap and easily available, short, simple and convenient to operate, low in waste water amount, high, green and environment-friendly, and facilitates industrial production. (by machine translation)