Description
Dotinurad is an organic compound with the chemical Name (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxidobenzo[d]thiazol-3(2H)-yl)methanone. This compound is a newer urate-lowering agent that suppresses uric acid reabsorption through the selective inhibition of urate transporter 1 (URAT1) in the proximal renal tubules, and it was first approved in Japan in 2020 for the treatment of hyperuricemia, irrespective of gout[1].
Uses
Dotinurad is a useful drug for treating hyperuricemia and gout.
Pharmacokinetics
The plasma concentration of dotinurad increased in a dose-dependent manner with Cmax and AUC0–24h values of 107 μg/ml and 780 μg.h/ml, respectively, at a dose of 30 mg/kg. Dotinurad dose-dependently lowered the plasma urate levels with its maximum effect at 8 h. Changes in plasma urate level between 0 and 8 h (ΔPUA) were lower than that of control by 0.28, 0.97 (p < 0.05), and 1.79 mg/dl (p < 0.01), at doses of 1, 5, and 30 mg/kg, respectively. Furthermore, dotinurad dose-dependently increased FEUA. The 0–4 h FEUA increased by 180%, at a dose of 30 mg/kg compared to the control (p < 0.01)[3].
Synthesis
Aminothiophenol (152) reacts with hydrated formaldehyde to give dihydrobenzothiazole 153. Acid chloride 155 is generated from acid 154. Dihydrobenzothiazole 153 is condensed with acid chloride 155 to form amide 156. Thiazole is oxidized using mCPBA. Methyl ether is removed in the presence of lithium chloride to give doxenolide.
Advantages
Dotinurad, as a selective urate reabsorption inhibitor, is anticipated to be more effective in inhibiting urate reabsorption compared to conventional urate-lowering agents. It demonstrates noninferiority to benzbromarone or febuxostat in reducing serum urate levels in hyperuricemic patients with or without gout. Moreover, its effectiveness remains uncompromised in patients with mild to moderate renal or hepatic impairment. In a long-term study, a majority of patients achieved the target serum urate level of ≤6 mg/dL when administered a maintenance dose of 2 or 4 mg once daily. No safety concerns, such as liver injury, were observed. Consequently, Dotinurad is expected to serve as a new therapeutic option for hyperuricemic patients, regardless of the presence of gout [2].
References
[1] Tanaka A, et al. Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA). European Journal of Medical Research, 2023; 238.
[2] Ishikawa T, et al. Dotinurad: a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia and gout. Expert Opinion on Pharmacotherapy, 2021; 22: 1397-1406.
[3] Taniguchi T, et al. Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor. Journal of Pharmacology and Experimental Therapeutics, 2019; 162-170.
