2. Academic Validation
  3. Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

  • Molecules. 2018 Jan 27;23(2):252. doi: 10.3390/molecules23020252.
Wenqing Cai 1 2,  Jingwei Wu 3,  Wei Liu 4,  Yafei Xie 5,  Yuqiang Liu 6,  Shuo Zhang 7,  Weiren Xu 8,  Lida Tang 9,  Jianwu Wang 10,  Guilong Zhao 11
Affiliations

Affiliations

  • 1 School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. [email protected].
  • 2 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 3 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 4 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 5 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 6 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 7 Shandong Key Laboratory for Special Silicon-Containing Materials, Advanced Materials Institute, Shandong Academy of Sciences, Jinan 250014, China. [email protected].
  • 8 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 9 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
  • 10 School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. [email protected].
  • 11 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. [email protected].
PMID: 29382075 DOI: 10.3390/molecules23020252
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 (1a-1x and 1ha-1hi) 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.

Keywords

URAT1 inhibitor; gout; hyperuricemia; lesinurad; structure-activity relationship (SAR); synthesis.

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