2. Academic Validation
  3. Synthesis, biological evaluation and 3D-QSAR studies of 1,2,4-triazole-5-substituted carboxylic acid bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia associated with gout

Synthesis, biological evaluation and 3D-QSAR studies of 1,2,4-triazole-5-substituted carboxylic acid bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia associated with gout

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):383-388. doi: 10.1016/j.bmcl.2018.12.036.
Jing-Wei Wu 1,  Ling Yin 2,  Yu-Qiang Liu 3,  Huan Zhang 4,  Ya-Fei Xie 3,  Run-Ling Wang 5,  Gui-Long Zhao 6
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
  • 2 Department of Chemistry and Chemical Engineering, Jining University, Qufu 273155, PR China.
  • 3 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, PR China.
  • 4 General Hospital, Tianjin Medical University, Tianjin 300052, PR China.
  • 5 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: [email protected].
  • 6 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, PR China. Electronic address: [email protected].
PMID: 30579795 DOI: 10.1016/j.bmcl.2018.12.036
Abstract

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 Inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 Inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 μM for 1g against human URAT1 vs 7.20 μM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.

Keywords

3D-QSAR; Bioisosteres; Biological evaluation; Gout; Synthesis.

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