Cabozantinib Malate

Details:

Using methyl 2-amino-4,5-dimethoxybenzoate as the raw material, 4-chloro-6,7-dimethoxyquinoline was prepared by cyclization and chlorination successively, and then reacted with p-aminophenol The nucleophilic substitution reaction yields 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (5) (or firstly react with p-nitrophenol and then reduce by palladium-carbon to obtain 5), 5 and After cyclopropane-1,1-dicarboxylic acid is condensed, it is reacted with p-fluoroaniline to prepare cabozantinib, and finally it is salted with (S)-malic acid (8) to obtain 1, and the total yield is low (< 20%) Pharmacological effects CabozantinibS-MALATE, formerly known as XL1Chemicalbook84, was developed by Exelixis Biopharmaceutical Company, USA. It mainly targets MET and VEGFR2 tyrosine kinases, which are related to the growth and spread of prostate cancer, to inhibit tumor metastasis and angiogenesis. Cabozantinib malate is the malate salt of Cabozantinib. It is an effective VEGFR2 inhibitor with IC50 of 0.035nM. It also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2 and AXL, with IC50 of respectively 1.3nM, 4nM, 4.6nM, 12nM/11.3nM/6nM, 14.3nM and 7nM.

Cabozantinib has weak inhibitory activity on RON and PDGFRβ, with IC50 of 124nM and 234nM, respectively, and weak activity on FGFR1 with IC50 of 5.294μM. Cabozantinib at low concentrations (0.1-0.5μM) is sufficient to significantly inhibit the production of constitutive and inducible Met phosphorylation in MPNST cells and the resulting downstream signal Chemicalbook, and inhibit HGF-induced MPNST cell migration and invasion. In cytokine-stimulated human umbilical vein endothelial cells (HUVECs), Cabozantinib also significantly inhibits the phosphorylation of Met and VEGFR2. Although Cabozantinib had no significant effect on the growth of MPNST cells at 0.1 μM, it significantly inhibited the growth of MPNST cells at 5-10 μM.