Design,Synthesis And Biological Evaluation Of VEGFR Inhibitors

Angiogenesis is the process of growing new blood vessels from existing vessels,which plays an important role in embryonic development and normal physiological activities.When an abnormal blood vessel is generated,it can lead to a series of diseases,such as atherosclerosis,retinal disease,endometriosis,arthritis and cancer,etc.Studies have indicated that angiogenesis plays an important role in the growth and metastasis of tumor.When the tumor diameter is greater than or equal to 2mm,it needs new blood vessels to provide nutrients and to remove metabolic waste to promote tumor growth and proliferation.The formation of new blood vessels are related to many growth factors,vascular endothelial growth factor（VEGF）and its receptor are the most important one among the growth factors.VEGF/VEGFR signaling pathway can regulate proliferation,migration,survival and permeability of endothelial cell,etc.VEGF/VEGFR plays a key role in the formation of new blood vessels,it can control the formation of new blood vessels by blocking the VEGF/VEGFR signaling pathway.Compared with the traditional anti-tumor drugs,the inhibitors of VEGFR have the following advantages:（1）Because endothelial cells in mature individuals do not divide,only in special circumstances（physiological cycle or trauma）they will be split,these kinds of drugs have little effect on normal cells;（2）The drug acts directly on the target blood cells;（3）It is not easy to produce drug resistance;（4）Drug action has amplification effect.Lenvatinib（E7080）is an oral multiple receptor tyrosine kinase（RTK）inhibitor developed by Eisai,it has best inhibiting activity on VEGFR-2（KDR）/VEGFR-3（Flt-4）,mostly for VEGFR2（KDR）/VEGFR3（Flt-4）with IC₅₀of 4n M/5.2 n M.The experiments,in vitro and in vivo,showed that lenvatinib can effectively inhibit the formation of new blood vessels.In February 2015,lenvatinib was approved by FDA for the treatment of invasive and differentiated thyroid cancer（DTC）.In the same year,FDA granted Lenvima breakthrough drug qualification（BTD）for the treatment of renal cell carcinoma（RCC）.At present,a gloubal multicenter,open-label,phase III trial is beening conducted to compare the efficacy and safety of lenvatinib（E7080）versus sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma.In this paper,we first summarized the structure-activity relationship of VEGFR inhibitors（QSR）and their structural characteristics,and then used lenvatinib as the template molecule to design three types of target molecules,（Fig.1）by adopting a strategy of combining traditional drug design and computer aided drug design technology,which aimed to get new inhibitors with novel structure and better inhibition on VEGFR-2.A method of preparing lenvatinib,with the characteristics of high efficiency,economical,safety and good yield,has been established by improving the synthesis route and optimizing reaction condition of lenvatinib.According to this method,the synthesis route of the target compound was designed,and 28 target compounds have been synthesized through 7 to 10 reaction steps.The structures of all the target compounds were confirmed by MS and ¹H-NMR.The lanthascreenassay（TR-FRET）method was used to determine the inhibitory activity of the 26 target compounds on VEGFR-2 kinase.The results showed that the inhibition rate of 18 tested compounds on VEGFR-2 kinase(IC₅₀value)was below 10n M,7 compounds had better inhibitory activity than that of the positive drug,and 11 compounds had equivalent inhibitory activity to the positive drug.Thus,some of the new compounds are worth of further study.The structure-activity relationship（QSR）of the new compounds has been summarized:For class I compounds,when the R substituent is benzene,and the C4 position of the benzene cycle was substituted by methyl or methoxy groups,or the C3 position of the benzene cycle substituted by-F or–Cl atoms,the compound will have higher activity;When R substituent is isoxazole or thiazole can significantly incresase the activity of the compound.For class II compounds,when the R substituent is benzene,and the C4 position of the benzene cycle was substituted by methyl groups,the compound will have higher activity.For classⅢcompounds,when the R substituent is benzene,and the C4position of the benzene cycle was substituted by-Cl or-NO₂groups,the compound will have higher activity.