Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.

Zean Zhao, Jin Liu, Peihua Kuang, Jian Luo, Goverdhan Surineni, Xiaolin Cen, Ting Wu, Ying Cao, Pingzheng Zhou, Jianxin Pang, Qun Zhang, Jianjun Chen

European journal of medicinal chemistry 2022 Feb 05

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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 their in vitro URAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC50 values ranging from 0.24 μM to 16.35 μM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC50 of 0.24 μM, comparable to that of verinurad (IC50 = 0.17 μM). KPH2f also inhibited GLUT9 with an IC50 value 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, cytotoxicity in vitro (lower than verinurad), and renal damage in 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. Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Citation

Zean Zhao, Jin Liu, Peihua Kuang, Jian Luo, Goverdhan Surineni, Xiaolin Cen, Ting Wu, Ying Cao, Pingzheng Zhou, Jianxin Pang, Qun Zhang, Jianjun Chen. Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia. European journal of medicinal chemistry. 2022 Feb 05;229:114092