Abstract
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg−1 · d−1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg−1 · d−1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
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27 January 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41401-022-00872-z
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81773794 and 81974507) and the Natural Science Foundation of Guangdong Province (2018A0303130088).
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JXP, YXT and JYG conceived and designed the research. ZAZ, YJ, YYC and QSL conducted the experiments. LL, YML YC and CTL analyzed the results. TW, YY and PZZ wrote the paper. All authors read and approved the paper.
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Zhao, Za., Jiang, Y., Chen, Yy. et al. CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia. Acta Pharmacol Sin 43, 121–132 (2022). https://doi.org/10.1038/s41401-021-00640-5
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DOI: https://doi.org/10.1038/s41401-021-00640-5
