1. 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.
- Author
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Wu JW, Yin L, Liu YQ, Zhang H, Xie YF, Wang RL, and Zhao GL
- Subjects
- Carboxylic Acids chemical synthesis, Carboxylic Acids chemistry, Dose-Response Relationship, Drug, Esters chemical synthesis, Esters chemistry, Gout metabolism, Humans, Hyperuricemia metabolism, Molecular Structure, Organic Anion Transporters metabolism, Organic Cation Transport Proteins metabolism, Triazoles chemistry, Carboxylic Acids pharmacology, Esters pharmacology, Gout drug therapy, Hyperuricemia drug therapy, Organic Anion Transporters antagonists & inhibitors, Organic Cation Transport Proteins antagonists & inhibitors, Quantitative Structure-Activity Relationship, Triazoles pharmacology
- 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 (IC
50 ). 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2019
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