Identification of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids as URAT1 inhibitors with hypouricemic effects

Abstract

Urate transporter 1 (URAT1) is a therapeutic target for the treatment of hyperuricemia and gout. However, the application of currently marketed URAT1 inhibitors is hampered by insufficient efficacy and poor safety profiles. A series of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids were designed by adopting strategies of molecular hybridization, scaffold hopping, and functional variation. Most compounds showed apparent inhibitory activity against URAT1, and the most active compound 7 exhibited an IC₅₀ of 0.18 μ M, which was comparable to the clinically available drug benzbromarone (IC₅₀ = 0.39 μ M). When tested in parallel with benzbromarone, compound 7 showed significant uric acid-lowering effect in a hyperuricemia zebrafish model induced by potassium oxonate and xanthine sodium salt. Compound 7 was also more metabolically stable than benzbromarone in mouse liver microsomes. The results suggested potential therapeutic benefits of these compounds in the treatment of hyperuricemia and gout.