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Molecules 2018, 23(2), 252; https://doi.org/10.3390/molecules23020252

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel 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
3
Shandong Key Laboratory for Special Silicon-Containing Materials, Advanced Materials Institute, Shandong Academy of Sciences, Jinan 250014, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 18 January 2018 / Revised: 25 January 2018 / Accepted: 26 January 2018 / Published: 27 January 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

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 (1a1x and 1ha1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors. View Full-Text
Keywords: gout; hyperuricemia; URAT1 inhibitor; lesinurad; structure-activity relationship (SAR); synthesis gout; hyperuricemia; URAT1 inhibitor; lesinurad; structure-activity relationship (SAR); 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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Cai, W.; Wu, J.; Liu, W.; Xie, Y.; Liu, Y.; Zhang, S.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor. Molecules 2018, 23, 252.

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