Design,Synthesis And Bioactivities Study Of Novel Human Uric Acid Transporter 1(h URAT1) Inhibitors

Uric acid is an antioxidant in the blood, but the high level of uric acid may result in some serious illness, such as hyperuricemia, gout and so on. Uric acid is the end product during the process of purine metabolism. Under the catalysis of xanthine oxidase, hypoxanthine is oxidized to xanthine, and then, xanthine will be transfered to uric acid. The excretion of uric acid depends on the secretion and reabsorption function of kidney, as a result, renal impairment and eating too much food including purine will increase serum uric acid level to lead to hyperuricemia.Recently there are two methods of the treatment of hyperuricemia, the first one is to use the xanthine oxidase inhibitors to inhibit the bioactivity of xanthine oxidase,and then, to reduce the biosynthesis of uric acid. The other method is to inhibit the bioactivity of URAT1 by URAT1 inhibitors, when the URAT1 is inhibited, the reabsorption of uric acid will be reduced to increased the excretion of uric acid. Based on clinical experience, xanthine oxidase inhibitors always bring about some serious side effects, so in this paper we pay main attention on the reserch of novol URAT1 inhibitors.In this study, two series of compounds was designed based on the structure of lesinuard which is a good URAT1 inhibitor under III Phase clinical trials from Ardea Biosciences company and some potentail URAT1 inhibitors lead compounds from some patents. 22 compounds have been synthesized and taken bioactivity tests using the HEK293 cell, what ’ s more,we compared their bioactivity data with lesinuard’s. The concentration of compounds is 100μM, we use the absorption rate of uric acid to represent the bioactivity of these compounds. I-4c which has the best bioactivity in them was confirmed as a novel URAT1 inhibitor lead compound, when the HEK293 cell was given 100μM of I-4c, its absorption rate of uric acid is 20.32%.