Design, Synthesis and Bioactivity of Highly Sterically Congested Flexible Uric Acid Transporter 1 (URAT1) Inhibitors

The flexible naphthyltriazolylmethane- bearing uric acid transporter 1 (URAT1) inhibitor 1 is a novel, highly potent drug candidate for the treatment of hyperuricemia and gout. In order to understand the effect of substituents at the CH2 linker between naphthalene and triazole rings on the bioactivity, 7 highly congested compounds 2a similar to 2g were designed and synthesized. All the synthesized compounds were characterized by H-1 NMR, C-13 NMR and HRMS, and their in vitro URAT1 inhibitory assay was studied. The results showed that the bioactivity decreased dramatically after the introduction of substituents to the CH2 linker, and among the synthesized compounds the bioactivity dropped as the flexibility of the molecules decreased, strongly indicating that any substituents at the CH2 linker were intolerable. The structure-activity relationship discovered here will be valuable to the design of URAT1 inhibitors.