Uses
Apatinib (YN968D1) is a small-molecule selective multitargeted tyrosine kinase inhibitor with an IC50 of 2.43 nM for the inhibition of VEGFR2.
Description
Apatinib is a tyrosine kinase inhibitor that potently suppresses the kinase activity of vascular endothelial growth factor 2 (VEGFR2; IC50 = 1 nM). It is less effective against c-kit (IC50 = 429 nM), Ret (IC50 = 13 nM), and c-src (IC50 = 53 nM) and does not inhibit EGFR, Her-2, or FGFR1 (IC50s = >10 μM). Apatinib has been shown to inhibit the proliferation, migration, and tube formation of human umbilical vein endothelial cells stimulated by fetal bovine serum and, either alone, or in combination with chemotherapeutic agents, prevented the growth of several established human tumor xenograft models.
Description
Apatinib mesylate, discovered by Advenchen Laboratories (United
States of America, USA) and co-developed by Jiangsu Hengrui
Medicine Co. Ltd (China), was approved by the Chinese Food and
Drug Administration (CFDA) in October 2014 for the treatment of
metastatic gastric carcinoma. Apatinib mesylate is an oral tyrosine
kinase inhibitor that selectively inhibits the vascular
endothelial growth factor receptor 2 (VEGFR2), which prevents new blood vessel formation selectively in tumor tissue. Apatinib
has shown inhibition of the VEGF signaling pathway with an IC50
value of 1 nM for VEGFR-2 in in vitro enzyme experiments. A
multicenter phase II study of apatinib is underway with patients
in non-triple-negative metastatic breast cancer trials. Non-clinical
studies concluded that apatinib may reverse the ATP-binding
cassette subfamily B member 1 and subfamily G member 2
(ABCB1- and ABCG2, respectively)-mediated multidrug resistance
which allows cancer cells to circumvent certain conventional antineoplastic
drugs, suggesting that apatinib could be effective as a
combination therapy.
Synthesis
The synthesis started
with commercially available 1-phenyl cyclopentane carbonitrile
(8), which was nitrated to provide nitrobenzene 9. Subsequent
reduction of 9 gave aniline 10, which was coupled with 2-chloronicotinoyl
chloride (11) to afford aryl amide 12. Subjection of the
2-pyridyl chloride within 12 to pyridin-4-ylmethanamine (13) in
hot pentanol gave 14. The preparation of apatinib 14 from starting
material 8 were reported on gram or milligram reaction scale with
no yield. 170 g of 14 was mixed with methylsulfonic acid in 95%
isopropanol¨CH2O solution to give 161.5 g of apatinib mesylate (II)
in 77% yield.
