Design, synthesis and biological evaluation of 2-[1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamido]benzoic acids as promising urate transporter 1 inhibitors with potential nephroprotective efficacy for the treatment of hyperuricemic nephropathy.

Hyperuricemic nephropathy (HN) is considered an important risk factor for mortality in patients with hyperuricemia. Reducing serum uric acid (UA) levels and mitigating kidney injury are essential components in the treatment of HN. Thus, UA-lowering drugs that can also protect the kidneys are urgently needed. We identified a urate transporter 1 (URAT-1) inhibitor, T29, with cytoprotective efficacy through screening an internal library against hyperuricemia using a UA-induced HK-2 cell injury model. A bioisosteric strategy was then employed to replace the indole core of T29 with pyrazole moieties; this resulted in a series of 2-[1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamido]benzoic acids. Among them, compound 18 demonstrated the best cytoprotective efficacy (cell viability = 92.2 % vs. model = 31.5 %), and the IC value of compound 18 against URAT-1 was 3.36 μM; both of these values exceeded T29. In an HN mice model induced by a 0.75 % adenine diet and intraperitoneal injection of potassium oxonate (400 mg/kg), compound 18 significantly reduced the serum UA levels by inhibiting URAT-1 activity. Furthermore, compound 18 improved kidney function by lowering serum creatinine (CRE) and urea nitrogen (BUN) levels while attenuating tubular dilation and inflammatory cell infiltration in the kidneys. Additionally, it suppressed the release of the proinflammatory cytokines IL-1β and TNF-α and reduced kidney fibrosis by downregulating the expression of α-SMA and TGF-β. In conclusion, compound 18 ameliorated HN by inhibiting URAT-1, alleviating immune-inflammatory responses and mitigating fibrosis; the results from this study demonstrate its potential as a therapeutic agent for HN.