Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 10, Pages 2017-2023Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00176
Keywords
Uricosurics; mitochondrial toxicity; benzbromarone; primary human renal proximal tubule epithelial cells; dotinurad
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To derive new uricosuric agents, novel phenol derivatives were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivatives with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compound 11 (dotinurad, FYU-981) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.
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