Design,Synthesis And The Activity Evaluation Of Phenyl Heterocyclic As XOR Inhibitors

Hyperuricemia is due to the high level of serum uric acid?sUA?,resulting in the deposition of monosodium urate crystals?MSU?in tissues or joints.The high level of sUA is generally caused by dysfunction of purine metabolism.Xanthine oxidoreductase?XOR?,a key enzyme in the purine metabolism,catalyzes the production of uric acid from hypoxanthine and xanthine.Therefore,inhibition of XOR can effectively reduce sUA levels to achieve the purpose of preventing and treating hyperuricemia.Currently,there are two main types of clinically available xanthine oxidoreductase inhibitors?XORIs?:purine and non-purine XORIs.Purine XORIs include allopurinol and its metabolite,oxipurinol,they showed many adverse effects during use,such as gastrointestinal discomfort,allergic reactions,renal failure,and hypersensitivity reactions.On the other hand,non-purine XORIs,represented by febuxostat and topiroxostat,have better uric acid lowering effect without serious adverse reactions,as compared with allopurinol.Unfortunately,their uric acid lowering effect is still not ideal for some patients,so there is pressing need for the further optimization and improvement of XORIsBased on our previous research results,the thesis mainly carried out the me-too optimization studies:1)Compounds of 4 type?Type A,B,C,D?were designed and 24 new compounds were synthesized,confirmed by ¹H NMR,¹³C NMR and HRMS,respectively;2)The results of in vitro XOR inhibition activity test showed most of the compounds were in the nanomolar level.Specially,the IC₅₀ values of compounds C₅ and D₁ were 8.0 nM and 7.2 nM,respectively,which were equivalent to febuxostat(IC₅₀=7.0 nM)?P>0.05?.The docking and QSAR analyse indicated that the binding mode of compounds C₅ and D₁ to XOR are not exactly the same as febuxostat;3)The potent hypouricemic effect of compounds C₅ and D₁was confirmed in two hyperuricemia mice models as acute hyperuricemia model mice and long-term hyperuricemia model mice.In addition,in the long-term hyperuricemia mice model,compounds C₅ and D₁ showed the advandage of decreasing urea nitrogen compared with febuxostat?P<0.05?,which suggested those two compounds may be a certain additional benefit in the improvement of kidney damage,the effect needs to be further systematic researched and verificated.