JOURNAL ARTICLE

Synthesis and bioevaluation of 1-phenyl-pyrazole-4-carboxylic acid derivatives as potent xanthine oxidoreductase inhibitors

Jing Li, Fangping Wu, Xingguo Liu, Yake Zou, Huixiong Chen, Zheng Li, Lei Zhang
European Journal of Medicinal Chemistry 2017 November 10, 140: 20-30
28918097
A diverse library of 1-phenyl-pyrazole-4-carboxylic acid derivatives were synthesized and evaluated for their inhibitory potency against xanthine oxidoreductase (XOR) in vitro and vivo, and the structure-activity relationship (SAR) analyses were also presented. Approximately half of the target compounds exhibited the inhibitory potency for XOR at the nanomolar level. Compounds 16c, 16d, and 16f emerged as the most potent xanthine oxidoreductase inhibitors with IC50 values of 5.7, 5.7 and 4.2 nM, respectively, in comparison to febuxostat (IC50 of 5.4 nM). Steady-state kinetics measurements indicated that 16c is a mixed-type inhibitor. A computer molecular docking study of 16c bound to XOR was performed to gain an insight into its bind mode and SAR for the series. A potassium oxonate-hypoxanthine-induced hyperuricemia model in mice was chosen to further confirm the hypouricemic effects of 16c and 16f, and the results demonstrated that 16c exhibits similar hypouricemic potency to febuxostat.

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