Journal Article

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

Xie, Yafei, Tang, Lida, Liu, Yuqiang, Wang, Jianwu, Liu, Wei, Shang, Qian, Xu, Weiren, Zhao, Guilong, Liu, Changying, Tian, He, Zhou, Zhixing

2016

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Arthritis / Butyric Acid - chemical synthesis / Butyric Acid - chemistry / Butyric Acid - pharmacology / Cell Line / Combinatorial Chemistry Techniques / gout / Humans / hyperuricemia / Inhibitory Concentration 50 / Laboratories / lesinurad / Molecular Structure / Organic Anion Transporters - antagonists & inhibitors / Organic Cation Transport Proteins - antagonists & inhibitors / Rheumatism / synthesis / URAT1 inhibitor / Uric acid