Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor.

In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit () derived from the replacement of the S atom in lesinurad with CH₂, 18 compounds (-) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, , which was 31-fold more potent than parent lesinurad (IC = 0.23 μM against human URAT1 for vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by , which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.