Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor.

Wenqing Cai,Lida Tang,Wei Liu,Jianwu Wang,Yuqiang Liu,Jingwei Wu,Guilong Zhao,Weiren Xu,Shuo Zhang,Yafei Xie

doi:10.3390/molecules23020252

Abstract

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a–1x and 1ha–1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

Highlights

Gout is the most common inflammatory arthritis caused by the deposition of monosodium urate (MSU) in articular and periarticular tissues and characterized by recurrent joint swelling, redness, warmth and severe pain [1]
The present study strongly suggested that diarylmethane backbone is a considerably promising molecular scaffold for the design of potent uric acid transporter 1 (URAT1) inhibitors
1h displayed an IC50 of 0.035 μM, which is 200- and 8-fold more potent than the parent lesinurad and benzbromarone, respectively, making it the most potent URAT1 inhibitor discovered in our laboratories so far and comparable to the most potent ones currently under development in clinical trials [18]

Summary

Introduction

Gout is the most common inflammatory arthritis caused by the deposition of monosodium urate (MSU) in articular and periarticular tissues and characterized by recurrent joint swelling, redness, warmth and severe pain [1]. If left untreated or poorly managed, tophaceous gout will lead to permanent joint destruction, bone erosion and kidney impairment, dramatically affecting patients’ quality of life and even threatening their lives [2]. More and more evidence has been accumulated to demonstrate that hyperuricemia is likely an independent risk factor for hypertension, chronic kidney disease (CKD) and congestive heart failure (CHF) among others [3,4]. First identified by Egyptians in 2640 BC, gout is among the earliest diseases recognized as a clinical entity [5]. The prevalence and incidence of hyperuricemia and gout have been rising worldwide [6,7], and gout and its comorbidities present significant burdens on both the individual and community [8,9].

Methods

Results

Conclusion