Discovery of novel benzbromarone analogs with improved pharmacokinetics and benign toxicity profiles as antihyperuricemic agents.
Discovery of novel benzbromarone analogs with improved pharmacokinetics and benign toxicity profiles as antihyperuricemic agents.
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DOI：
10.1016/j.ejmech.2022.114682
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发表时间：
2022-08
影响因子：
6.7
通讯作者：
Zean Zhao;Jin Liu;Lin Yuan;Zichao Yang;Peihua Kuang;Hui Liao;Jian Luo;H. Feng;Fengxin Zheng;Yongjun Chen;Ting Wu;Jiayin Guo;Ying Cao;Yang Yang-Yang;Cui-ting Lin;Qun Zhang;Jianjun Chen;Jianxin Pang
中科院分区：
文献类型：
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作者：
Zean Zhao;Jin Liu;Lin Yuan;Zichao Yang;Peihua Kuang;Hui Liao;Jian Luo;H. Feng;Fengxin Zheng;Yongjun Chen;Ting Wu;Jiayin Guo;Ying Cao;Yang Yang-Yang;Cui-ting Lin;Qun Zhang;Jianjun Chen;Jianxin Pang
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 IC50values ranging from 5.83 μM to 0.80 μM. Among them,JNS4exhibited the highest URAT1 inhibitory activity with an IC50of 0.80 μM, comparable to that of BM (IC50= 0.53 μM). Molecular dynamic simulations showed thatJNS4formed π-cation interaction with R477, the same as BM. Different from BM,JNS4bound to W357 and H245viaπ-π interactions and formed a hydrogen bond with S35, which might contribute to the high URAT1 binding affinity ofJNS4.JNS4hardly inhibited GLUT9 (IC50> 20 μM), another urate reabsorption transporter. In addition,JNS4showed little inhibitory effects against OAT1 and ABCG2 with IC50of 4.04 μM and 10.16 μM, respectively. Importantly,JNS4displayed higherin vivourate-lowering effects at doses of 1–4 mg/kg in a mouse model of hyperuricemia, as compared to BM and lesinurad. Furthermore,JNS4possessed favorable pharmacokinetic properties with an oral bioavailability of 55.28%, significantly higher than that of BM (36.11%). Moreover,JNS4demonstrated benign toxicity profiles (no cytotoxicities against HepG2 and HK2 cells; no hepatic and renal toxicities observedin vivo). Collectively, these results suggest thatJNS4represents a novel, safe and selective URAT1 inhibitor with excellent druggabilities and is worthy of further investigation as ananti-hyperuricemic agent.
