Identification of 5-[5-cyano-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamido] thiazole-4-carboxylic acid as a promising dual inhibitor of urate transporter 1 and xanthine oxidase

In combination with allopurinol, tranilast is used as an urate transporter 1 (URAT1) inhibitor for the treatment of hyperuricemia, but its structure-activity relationship concerning URAT1 inhibitory activity is rarely studied. In this paper, analogs 1–30 were designed and synthesized using scaffold hopping strategy on the basis of tranilast and the privileged scaffold indole. Then, URAT1 activity was evaluated using 14C-uric acid uptake assay with HEK293-URAT1 overexpressing cells. Compared with tranilast (inhibitory rate = 44.9% at 10 μM), most compounds displayed apparent inhibitory effects, ranging from 40.0% to 81.0% at 10 μM on URAT1. Surprisingly, along with the bringing in of a cyano group at the 5-position of indole ring, compounds 26 and 28–30 exerted xanthine oxidase (XO) inhibitory activity. In particular, compound 29 presented potency on URAT1 (48.0% at 10 μM) and XO (IC50 = 1.01 μM). Molecular simulation analysis revealed that the basic structure of compound 29 had an affinity with URAT1, and XO. Furthermore, compound 29 demonstrated a significant hypouricemic effect in a potassium oxonate-induced hyperuricemia rat model at an oral dose of 10 mg/kg during in vivo tests. In summary, tranilast analog 29 was identified as a potent dual-target inhibitor of URAT1 and XO, and a promising lead compound for further investigation.