摘要 : In order to systematically explore and better understand the structure-activity relationship(SAR)of a diarylmethane backbone in the design of potent uric acid transporter 1(URAT1)inhibitors,33 compounds(1a-1x and 1ha-1hi)were desi... 展开 In order to systematically explore and better understand the structure-activity relationship(SAR)of a diarylmethane backbone in the design of potent uric acid transporter 1(URAT1)inhibitors,33 compounds(1a-1x and 1ha-1hi)were designed and synthesized,and their in vitro URAT1inhibitory activities(IC_(50))were determined.The three-round systematic SAR exploration led to thediscovery of a highly potent novel URAT1 inhibitor,1h,which was 200-and 8-fold more potentthan parent lesinurad and benzbromarone,respectively(IC_(50)= 0.035 μM against human URAT1 for1h vs.7.18 μM and 0.28 μM for lesinurad and benzbromarone,respectively).Compound 1h is themost potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the mostpotent ones currently under development in clinical trials.The present study demonstrates that thediarylmethane backbone represents a very promising molecular scaffold for the design of potentURAT1 inhibitors. 收起