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Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-08 , DOI: 10.1021/acs.jmedchem.0c00223 Tong Zhao 1 , Qing Meng 1 , Zhuosen Sun 1 , Yanyu Chen 2 , Wei Ai 1 , Zean Zhao 2 , Dongwei Kang 1 , Yue Dong 1 , Ruipeng Liang 1 , Ting Wu 2 , Jianxin Pang 2 , Xinyong Liu 1 , Peng Zhan 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-08 , DOI: 10.1021/acs.jmedchem.0c00223 Tong Zhao 1 , Qing Meng 1 , Zhuosen Sun 1 , Yanyu Chen 2 , Wei Ai 1 , Zean Zhao 2 , Dongwei Kang 1 , Yue Dong 1 , Ruipeng Liang 1 , Ting Wu 2 , Jianxin Pang 2 , Xinyong Liu 1 , Peng Zhan 1
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Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC50 = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
中文翻译：
新型人类尿酸盐转运蛋白1抑制剂，具有良好的可成药性，为低血钾药物候选者。
Lesinurad是一种人类尿酸盐转运蛋白1（URAT1）抑制剂，已于2015年被批准用作治疗与痛风相关的高尿酸血症的药物，可引起肝和肾毒性。在这里，我们通过应用支架跳跃，生物等排体和取代基修饰策略来修饰lesinurad的所有三个结构成分。在急性高尿酸血症的小鼠模型中，有21种合成化合物显示出增加的降低血清尿酸（SUA）的活性；SUA是约4倍的与处理的动物低44，54，和83与lesinurad或苯溴马隆比较。在URAT1抑制试验，44是在8倍lesinurad更有效（IC 50：μM1.57 VS 13.21μM）。值得注意的是83也显示出对GLUT9的有效抑制活性（IC 50 = 31.73μM）。此外，我们还初步探讨了手性对有前途的衍生物44和54效力的影响。化合物44，54，和83显示出良好的药物样药代动力学和似乎是有希望的高尿酸血症和痛风的治疗的候选者。
更新日期：2020-10-08
中文翻译：
新型人类尿酸盐转运蛋白1抑制剂，具有良好的可成药性，为低血钾药物候选者。
Lesinurad是一种人类尿酸盐转运蛋白1（URAT1）抑制剂，已于2015年被批准用作治疗与痛风相关的高尿酸血症的药物，可引起肝和肾毒性。在这里，我们通过应用支架跳跃，生物等排体和取代基修饰策略来修饰lesinurad的所有三个结构成分。在急性高尿酸血症的小鼠模型中，有21种合成化合物显示出增加的降低血清尿酸（SUA）的活性；SUA是约4倍的与处理的动物低44，54，和83与lesinurad或苯溴马隆比较。在URAT1抑制试验，44是在8倍lesinurad更有效（IC 50：μM1.57 VS 13.21μM）。值得注意的是83也显示出对GLUT9的有效抑制活性（IC 50 = 31.73μM）。此外，我们还初步探讨了手性对有前途的衍生物44和54效力的影响。化合物44，54，和83显示出良好的药物样药代动力学和似乎是有希望的高尿酸血症和痛风的治疗的候选者。
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