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- Title
Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor.
- Authors
He Tian; Wei Liu; Zhixing Zhou; Qian Shang; Yuqiang Liu; Yafei Xie; Changying Liu; Weiren Xu; Lida Tang; Jianwu Wang; Guilong Zhao
- Abstract
In order to systematically explore and understand the structure–activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a–1r) 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, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, 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.
- Publication
Molecules, 2016, Vol 21, Issue 11, p1543
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules21111543