Abstract
In order to systematically explore and understand the structure–activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a–1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.
Highlights
Gout, which is characterized by recurrent joint swelling and pain, is the most prevalent form of inflammatory arthritis
The systematic structure–activity relationship (SAR) exploration led to the discovery of 1q as a highly potent uric acid transporter 1 (URAT1) inhibitor, which was 31-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay (IC50 = 0.23 μM against human URAT1 for 1q vs. 7.18 μM for lesinurad)
URAT1 inhibitor, 1q, which was 31-fold more potent than the parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs. 7.18 μM for lesinurad)
Summary
Gout, which is characterized by recurrent joint swelling and pain, is the most prevalent form of inflammatory arthritis It is caused by the deposition of monosodium urate (MSU) in joints and soft tissues [1]. The fundamental of treatment of gout is to dissolve MSU crystals by urate-lowering therapy (ULT) with xanthine oxidase inhibitors (XOIs) such as allopurinol and febuxostat, uricosuric agents such as probenecid, sulfinpyrazone, and benzbromarone, and uricase such as pegloticase [13,14]. Given the fact that 90% of the patients with hyperuricemia are urate under-excretors, URAT1 inhibitors, which lower sUA by inducing uricosuria, were believed to be a very promising class of uricosuric agents for the treatment of hyperuricemia and gout [18].
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