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Molecules 2016, 21(11), 1543; doi:10.3390/molecules21111543

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

1
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
2
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Received: 24 October 2016 / Revised: 9 November 2016 / Accepted: 10 November 2016 / Published: 16 November 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1636 KB, uploaded 16 November 2016]   |  

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 (1a1r) 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. View Full-Text
Keywords: gout; hyperuricemia; URAT1 inhibitor; lesinurad; synthesis gout; hyperuricemia; URAT1 inhibitor; lesinurad; synthesis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Tian, H.; Liu, W.; Zhou, Z.; Shang, Q.; Liu, Y.; Xie, Y.; Liu, C.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor. Molecules 2016, 21, 1543.

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