Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.
Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.
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DOI：
10.1016/j.ejmech.2021.114092
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发表时间：
2021-12
影响因子：
6.7
通讯作者：
Zean Zhao;Jin Liu;Peihua Kuang;Jian Luo;G. Surineni;Xiaolin Cen;Ting Wu;Ying Cao;Pingzheng Zhou;Jianxin Pang;Qun Zhang;Jianjun Chen
中科院分区：
文献类型：
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作者：
Zean Zhao;Jin Liu;Peihua Kuang;Jian Luo;G. Surineni;Xiaolin Cen;Ting Wu;Ying Cao;Pingzheng Zhou;Jianxin Pang;Qun Zhang;Jianjun Chen
Verinurad(RDEA3170)是一种选择性URAT1抑制剂，正在研究中，用于治疗痛风和高尿酸血症。为了进一步改善马鞭草的药效学和药代动力学，增加其结构的多样性，我们设计了新的马鞭草类似物，通过在萘和吡啶环之间引入连接基(例如氨甲基、氨基或氧)来增加柔韧性。合成了这些化合物，并测试了它们的维生素UAT1抑制活性。大部分化合物对URAT1具有较强的抑制活性，IC50值在0.24万μM~16.35万μM之间，其中化合物KPH2f对URAT1的抑制活性最高，其IC50值为0.24万μM，与马鞭草相当(IC50值为0.17μM)。KPH2f对GLUT9也有抑制作用，IC50值为9.37±7.10μM，表明KPH2f具有双重靶向作用。此外，KPH2f对OAT1和ABCG2几乎没有影响，因此不太可能引起OAT1/ABCG2介导的药物-药物相互作用和/或中和URAT1/GLUT9抑制剂的尿酸效应。重要的是，与Verinurad(10 mg/kg)相比，KPH2f(10 mg/kg)在降低血清尿酸水平方面同样有效，并且在小鼠高尿酸血症模型中表现出更高的尿酸效应。此外，KPH2f具有良好的药代动力学特性，口服生物利用度为30.13%，明显优于马鞭草(21.47%)。此外，KPH2f具有良好的安全性，在体外不会引起Herg毒性，在体外(低于马鞭草)具有细胞毒性，在体内不会造成肾脏损害。综上所述，这些结果表明KPH2f是一种新型、安全、有效的URAT1/GLUT9双重抑制剂，具有更好的药效性，值得作为抗高尿酸血症候选药物进行进一步研究。
Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia. In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g. aminomethyl, amino or oxygen) between the naphthalene and the pyridine ring to increase the flexibility. These compounds were synthesized and tested for theirin vitroURAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC50values ranging from 0.24 μM to 16.35 μM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC50of 0.24 μM, comparable to that of verinurad (IC50= 0.17 μM). KPH2f also inhibited GLUT9 with an IC50value of 9.37 ± 7.10 μM, indicating the dual URAT1/GLUT9 targeting capability. In addition, KPH2f showed little effects on OAT1 and ABCG2, and thus was unlikely to cause OAT1/ABCG2-mediated drug-drug interactions and/or to neutralize the uricosuric effects of URAT1/GLUT9 inhibitors. Importantly, KPH2f (10 mg/kg) was equally effective in reducing serum uric acid levels and exhibited higher uricosuric effects in a mice hyperuricemia model, as compared to verinurad (10 mg/kg). Furthermore, KPH2f demonstrated favorable pharmacokinetic properties with an oral bioavailability of 30.13%, clearly better than that of verinurad (21.47%). Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicityin vitro(lower than verinurad), and renal damagein vivo. Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate.