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 |
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| Authors: | Jing-wei Wu Ling Yin Yu-qiang Liu Huan Zhang Ya-fei Xie Run-ling Wang Gui-long Zhao |
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| Institution: | 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 |
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| 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. |
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| Keywords: | Synthesis Biological evaluation 3D-QSAR Bioisosteres Gout |
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