Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout

Title:Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout

Volume: 13 Issue: 3

Author(s): Xiansheng Zhang, Jingwei Wu, Wei Liu, Yuqiang Liu, Yafei Xie, Qian Shang, Zhixing Zhou, Weiren Xu, Lida Tang, Jianwu Wang and Guilong Zhao*

Affiliation:

• Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 308 An Shan Xi Dao, Nankai District, Tianjin 300193,China

Keywords: Gout, hyperuricemia, URAT1 inhibitor, lesinurad, flexible, synthesis.

Abstract: Background: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy.

Objective: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor.

Methods: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1.

Results: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad).

Conclusion: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.

Cite this article as:

Zhang Xiansheng, Wu Jingwei, Liu Wei, Liu Yuqiang, Xie Yafei, Shang Qian, Zhou Zhixing, Xu Weiren, Tang Lida, Wang Jianwu and Zhao Guilong*, Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout, Medicinal Chemistry 2017; 13 (3) . https://dx.doi.org/10.2174/1573406412666160915163002

DOI https://dx.doi.org/10.2174/1573406412666160915163002	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638