Human Uric Acid Transporter 1 (hURAT1): An Inhibitor Structure–Activity Relationship (SAR) Study

Abstract

The current study describes the chemical synthesis of a series of (2-ethylbenzofuran-3-yl)(substituted-phenyl)methanone compounds and their subsequent in vitro testing via oocytes expressing hURAT1. The experimental data support the notion that a potent hURAT1 inhibitor requires an anion (i.e., a formal negative charge) to interact with the positively charged hURAT1 binding pocket. An anion appears to be a primary requirement in order to be a hURAT1 substrate (i.e., urate) or inhibitor. We discuss the inhibitor structure–activity relationship and how electronically donating or withdrawing groups attached to the B-ring can decrease or increase inhibitory potency, respectively.

Keywords:

• Human uric acid transporter 1 (hURAT1
• SLC22A12)
• inhibitor study
• structure–activity relationship (SAR)

Acknowledgments

The research was funded by J-Pharma Co., Ltd. (Tokyo, Japan.) and also utilized services of the Medicinal Chemistry Core facility (MCC; MFW) housed within the Department of Pharmaceutical Sciences (DOPS). In part, the MCC has been funded via Colorado Clinical and Translational Sciences Institute grant 5UL1RR025780 from the National Center for Research Resources at the National Institutes of Health (NCRR/NIH).