Discovery of novel benzbromarone analogs with improved pharmacokinetics and benign toxicity profiles as antihyperuricemic agents.

Benzbromarone (BM) is a potent URAT1 inhibitor approved for the treatment of gout. However, the low URAT1-selectivity and hepatotoxcity limit its clinical use. To solve these problems, we rationally designed and synthesized a series of BM derivatives by chemotype hybridization and bioisosteric replacement. Most compounds exhibited potent inhibitory activities against URAT1 with IC 50 values ranging from 5.83 μM to 0.80 μM. Among them, JNS4 exhibited the highest URAT1 inhibitory activity with an IC 50 of 0.80 μM, comparable to that of BM (IC 50 = 0.53 μM). Molecular dynamic simulations showed that JNS4 formed π-cation interaction with R477, the same as BM. Different from BM, JNS4 bound to W357 and H245 via π-π interactions and formed a hydrogen bond with S35, which might contribute to the high URAT1 binding affinity of JNS4. JNS4 hardly inhibited GLUT9 (IC 50 > 20 μM), another urate reabsorption transporter. In addition, JNS4 showed little inhibitory effects against OAT1 and ABCG2 with IC 50 of 4.04 μM and 10.16 μM, respectively. Importantly, JNS4 displayed higher in vivo urate-lowering effects at doses of 1–4 mg/kg in a mouse model of hyperuricemia, as compared to BM and lesinurad. Furthermore, JNS4 possessed favorable pharmacokinetic properties with an oral bioavailability of 55.28%, significantly higher than that of BM (36.11%). Moreover, JNS4 demonstrated benign toxicity profiles (no cytotoxicities against HepG2 and HK2 cells; no hepatic and renal toxicities observed in vivo). Collectively, these results suggest that JNS4 represents a novel, safe and selective URAT1 inhibitor with excellent druggabilities and is worthy of further investigation as an anti -hyperuricemic agent. [Display omitted] • Novel benzbromarone (BM) analogs were discovered as an anti -hyperuricemic agents. • JNS4 showed the highest URAT1 inhibitory activity with IC 50 of 0.80 μM. • JNS4 displayed higher in vivo urate-lowering efficacy than BM and lesinurad. • JNS4 demonstrated an oral bioavailability of 55.28%, better than BM (36.11%). • JNS4 exhibited benign toxicity profiles with little/no hepato-/nephron-toxicity. [ABSTRACT FROM AUTHOR]