Design, Synthesis, And Activity Evaluation Of Reducing Uric Acid Of Xor Inhibitors

The xanthine oxidoreductase?XOR?,a key enzyme in purine catabolism,is generally recognized as a target enzyme in gout treatment.It has been reported that the inhibition of XOR could reduce the levels of plasma uric acid against gout and hyperuricemia.Up to now,the xanthine oxidoreductase inhibitors?XORIs?mainly include two classes:1)purine XORIs,e.g.,allopurinol and oxipurinol.Those drugs have obvious defects that they demonstrate so many side effects,such as hepatotoxicity,acute renal failure,aplasticanemia and hypersensitivity syndrome;2)non-purine XORI,febuxostat has advantages of the therapeutic effect,safety of dose and bioavailability than purine XORIs.When it approved by FDA in2009,the annual growth rate of its sales is close to 20%,with global sales reached$296million in 2015,suggestting that the new non-purine XORIs have great market.Due to above reasons,according to febuxostat,the existing patent protection and known structure-activity relationship of anti-gout drug,1)3 types of new XORIs were designed,25compounds had been synthesized,including 23 new compounds?verified by scifinder?.All new compounds were characterized by ¹H-NMR,¹³C-NMR,HR-MS and IR;2)It is found that IC₅₀ value of 13 compounds exhibited about nanomolar range in the XOR inhibitory activity tests in vitro.Specially the IC₅₀ of compounds B₃,B₄,and B₆ are 5.7,5.7 and 4.2 nM,respectively,in comparison to febuxostat(IC₅₀=5.4 nM);3)based on the XOR inhibitory activity in vitro,the structure-activity relationship was discussed and the virtual docking was carried out,it could be considered that the reported structure-activity relationship of febuxostat is not fully applicable to those new XORIs,moreover the binding model of them to XOR are not exactly same compared with febuxostat to XOR;4)the uric-acid-lowering activity of compounds B₃ and B₆ were evaluated in two hyperuricemia mice models,the results suggested that B₃ can significantly reduce the blood uric acid level at 1 h after the treatment in acute hyperuricemia mice model,similar to febusxotat;also,B₃ exhibited equal hypouricemic potency to that of febuxostat after administration in weekly hyperuricemia mice model.