Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016–2019)

ABSTRACT

Introduction: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insufficient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion.

Areas covered: In this review, the authors addressed the patent applications (2016–2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents.

Expert opinion: Substituent decorating, bioisosterism, and scaffold hopping are three common medicinal chemistry strategies used in the discovery of URAT1 inhibitors. Meanwhile, the introduction of sulfonyl group into small molecules has become one of the important strategies for structural optimization of URAT1 inhibitors. Furthermore, developing drug candidates targeting both URAT1 and xanthine oxidase (XOD) has attracted lots of interest and attention.

KEYWORDS:

• URAT1 inhibitors
• lesinurad
• RDEA3170
• SHR4640
• benzbromarone
• sulfonamide
• dual inhibitor
• gout
• hyperuricemia

Article highlights

• Focus on the design and synthesis of URAT1 inhibitors continues to be an area of interest.

• This review covers the patents describing the discovery and development of novel URAT1 inhibitors from 2016 to 2019.

• Substituent decorating, bioisosterism, and scaffold hopping are important approaches for seeking novel anti-gout agents.

• The introduction of sulfonyl group into small molecules has displayed significant URAT1 inhibitory potential.

• Dual XOD and URAT1 inhibitors is a promising approach to treat hyperuricemia and gout.

• The trends and promising prospects of URAT1 inhibitors are presented.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Key Project of NSFC for International Cooperation [grant number 81420108027]; the National Natural Science Foundation of China (NSFC) [grant number 81273354], [grant number 81573347]; Young Scholars Program of Shandong University (YSPSDU) [grant number 2016WLJH32]; and Key Research and Development Project of Shandong Province [grant number 2017CXGC1401].