Pharmacological evaluation of a novel skeleton compound isobavachin (4',7-dihydroxy-8-prenylflavanone) as a hypouricemic agent: Dual actions of URAT1/GLUT9 and xanthine oxidase inhibitory activity.
Pharmacological evaluation of a novel skeleton compound isobavachin (4',7-dihydroxy-8-prenylflavanone) as a hypouricemic agent: Dual actions of URAT1/GLUT9 and xanthine oxidase inhibitory activity.
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DOI：
10.1016/j.bioorg.2023.106405
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发表时间：
2023-02
影响因子：
5.1
通讯作者：
Zean Zhao;J. Luo;Hui Liao;Fengxin Zheng;Xinhua Chen;Jiajun Luo;Yongjun Chen;Kunlu Zhao;Shuqin Zhang;Jinhong Tian;Ting Wu;Yongmei Li;Lu Li;Yang Yang-Yang;Cui-ting Lin;Qun Zhang;Yuan-xin Tian;Jianxin Pang
中科院分区：
文献类型：
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作者：
Zean Zhao;J. Luo;Hui Liao;Fengxin Zheng;Xinhua Chen;Jiajun Luo;Yongjun Chen;Kunlu Zhao;Shuqin Zhang;Jinhong Tian;Ting Wu;Yongmei Li;Lu Li;Yang Yang-Yang;Cui-ting Lin;Qun Zhang;Yuan-xin Tian;Jianxin Pang
在此之前，我们发现了一种新的天然支架化合物，异巴伐辛（4′，7-二羟基-8-烯基黄烷酮），基于优点筛选方法，从形状和结构上看，它是一种有效的URAT1抑制剂。本研究进一步探讨了异巴伐辛的降尿酸机制、药代动力学和毒性。异巴伐辛抑制URAT1的ic50值为0.24±0.06 μM， URAT1的残基S35、F365、I481和R477对异巴伐辛具有较高的亲和力。异巴伐辛还能抑制葡萄糖转运蛋白9 (GLUT9)，这是另一个关键的尿酸重吸收转运蛋白，ic50值为1.12±0.26 μM。分子对接和MMGBSA结果表明，异巴伐辛可能与尿酸竞争R171、L75和N333残基，从而抑制GLUT9的尿酸转运。异巴瓦辛对尿酸分泌转运体OAT1、OAT3和ABCG2的ic50分别为4.38±1.27 μM、3.64±0.62 μM和10.45±2.17 μM。异巴伐辛在体外抑制黄嘌呤氧化酶（XOD）活性，ic50值为14.43±3.56 μM，在体内抑制5 ~ 20 mg/kgin的肝脏XOD活性。对接和MMGBSA分析表明，异巴伐辛可能与XOD的Mo-Pt催化中心结合，从而抑制尿酸的产生。在体内，与阳性药物莫宁（20 mg/kg）和RDEA3170 （10 mg/kg）相比，异巴伐辛在5-20 mg/kg的剂量下表现出强大的降尿酸和降尿作用。安全性评价表明异巴伐辛是安全的，无明显的毒性。MTT试验表明异巴伐辛对HK2细胞毒性很小。在体内，用50 mg/kg异巴伐辛治疗14天后，血清CR/BUN水平显示异巴伐辛肾毒性很小，ALT/AST水平显示无肝毒性。进一步HE检查也提示异巴伐辛没有明显的肾/肝损害。SD大鼠药代动力学研究表明，异巴伐辛具有较低的生物利用度（12.84±5.13%），但其维持血药浓度的半衰期较长（7.04±2.68 h）。综上所述，这些结果表明，异巴伐辛作为抗高尿酸血症的候选药物值得进一步研究，其新的作用机制是：选择性尿酸盐重吸收抑制剂（URAT1/GLUT9），对XOD具有中等抑制作用。
Previously we discovered a novel natural scaffold compound, isobavachin (4′, 7-dihydroxy-8-prenylflavanone), as a potent URAT1 inhibitor by shape and structure based on a virtue screening approach. In this study, further urate-lowering mechanism, pharmacokinetics and toxicities of isobavachin were conducted. Isobavachin inhibited URAT1 with an IC50value of 0.24 ± 0.06 μM, and residues S35, F365, I481 and R477 of URAT1 contributed to high affinity for isobavachin. Isobavachin also inhibited glucose transporter 9 (GLUT9), another pivotal urate reabsorption transporter, with an IC50value of 1.12 ± 0.26 μM. Molecular docking and MMGBSA results indicated that isobavachin might compete residues R171, L75 and N333 with uric acid, which leads to inhibition of uric acid transport of GLUT9. Isobavachin weakly inhibited urate secretion transporters OAT1 with an IC50value of 4.38 ± 1.27 μM, OAT3 with an IC50of 3.64 ± 0.62 μM, and ABCG2 with an IC50of 10.45 ± 2.17 μM. Isobavachin also inhibited xanthine oxidase (XOD) activityin vitrowith an IC50value of 14.43 ± 3.56 μM, and inhibited the hepatic XOD activities at 5–20 mg/kgin vivo. Docking and MMGBSA analysis indicated that isobavachin might bind to the Mo-Pt catalyze center of XOD, which leads to inhibition of uric acid production.In vivo, isobavachin exhibited powerful urate-lowering and uricosuric effects at 5–20 mg/kg compared with the positive drugs morin (20 mg/kg) and RDEA3170 (10 mg/kg). Safety assessments revealed that isobavachin was safe and had no obvious toxicities. Isobavachin has little cell toxicity in HK2 cells as indicated by the MTT assay.In vivo,after treatment with 50 mg/kg isobavachin for 14 days, isobavachin had little renal toxicity, as revealed by serum CR/BUN levels, and no hepatotoxicity as revealed by ALT/AST levels. Further HE examination also suggests that isobavachin has no obvious kidney/liver damage. A pharmacokinetic study in SD rats indicated isobavachin had lower bioavailability (12.84 ± 5.13 %) but long half-time (7.04 ± 2.68 h) to maintain a continuous plasma concentration. Collectively, these results indicate that isobavachin deserves further investigation as a candidate anti-hyperuricemic drug with a novel mechanism of action: selective urate reabsorption inhibitor (URAT1/GLUT9) with a moderate inhibitory effect on XOD.