Me-too Drug Design,Synthesis And Kinase Inhibitory Activity Research Based On The Linifanib

Me-too drug development is a kind of follow-up drug discovery strategy which can quickly obtain the strong activity and low toxicity candidate drug molecules that come from structure modification of clinical phase III stage or marketed drugs, called lead compounds. Compared with pioneering innovative drug development, it is a less difficult and risky but more successful way, and is classified as an important and practical approach in drug research. Abbott Laboratories has developed a series of RTK inhibitors including Linifanib, one of the most promising candidate compounds, which can specifically inhibit vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) family of tyrosine kinase (TK) activity in the nanomolar levels. In order to obtain novelty Linifanib analogues possessing independent intellectual property right, we designed two types of novel N,N’-aryl substituted urea skeletons derived from Linifanib, under the premise of employing as small as possible changes. A total of 40 derivatives (A01-A40) containing these two skeletons were synthesized, and all derivatives were tested in three pro-angiogenic kinase inhibitory assays (PDGFR-a, FGFR-1 and EGFR-2). The results indicated that 15 derivatives showed good inhibitory activities against PDGFR-a (IC50<1μM),12 derivatives showed moderate inhibitory activities against FGFR-1 (1μM<IC50<10μM), and 18 derivatives showed moderate inhibitory activities against VEGFR-2 (IC50<10μM), including 3 derivatives with good inhibitory activities against VEGFR-2 (IC50<1μM). It is noteworthy that derivatives A27-A28 and A38 show, to a certain degree, broad-spectrum kinase inhibitory properties. Considering the novelty and similar structure compared with Linifanib, these three derivatives may serve as a reasonable lead compound for further developments. On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of these 40 derivatives, which give some valuable clues for further design and development of me-too anti-cancer drug of Linifanib.