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.

Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

“…As illustrated in Figure 1, we probed three different benzofuran templates (I, II, and III) and their ability to inhibit 14 C-urate uptake in oocytes expressing hURAT1. Our previous work provided important insights regarding required chemical features; in summary, the data supported the notion that an anion (preferably on the C-ring; Figure 1) is required in order to interact with a positively charged hURAT1 binding pocket 10,11. The previous studies also demonstrated how electronic donating and/or withdrawing groups attached to the B-ring influence inhibitory potency.…”

“…Di-methyl (15) had an in vitro IC 50 of approximately 7.5 μM, whereas (14) was a much weaker inhibitor (.25 μM). We also synthesized methoxy ether (16), a molecule that does not produce the corresponding anion; thus, (16) is a C-ring methoxy analog of benzbromarone 1 11. Compound 16 was a much weaker inhibitor, ~47-fold (1.2 μM versus 26 nM).…”

“…We have prepared and tested additional (2-alkyl-benzofuran-3-yl)(3,4,5-substituted-phenyl)methanone compounds not previously described 10,11. Three constitutional isomer templates (Figure 1) were probed; compounds (1)–(19), (20)–(22), and (23)–(26) are template I, II, and III examples, respectively.…”

“…Synthesis of the following compounds has been described previously: (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone (1), (2-ethyl-5-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone (2), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methoxybenzofuran-3-yl)methanone (3), (5-bromo-2-ethyl-6-methoxybenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (4), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxybenzofuran-3-yl)methanone (5), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxybenzofuran-3-yl)methanone (6), (4,6-dibromo-2-ethyl-5-hydroxybenzofuran-3-yl)(4-methoxyphenyl)methanone (7), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-hydroxybenzofuran-3-yl)methanone (8), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-fluorobenzofuran-3-yl)methanone (9), (2-ethylbenzofuran-3-yl)(3-fluoro-4-hydroxyphenyl)methanone (10), (3-chloro-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone (11), (3-bromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone (12), (2-ethyl-5-methoxybenzofuran-7-yl)(4-methoxyphenyl)methanone (20), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxybenzofuran-7-yl)methanone (21), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-hydroxybenzofuran-7-yl)methanone (22), (6-bromo-2-ethyl-7-hydroxybenzofuran-4-yl)(4-methoxyphenyl)methanone (23), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxybenzofuran-4-yl)methanone (24), (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-hydroxybenzofuran-4-yl)methanone (25), (6-bromo-2-ethyl-7-hydroxybenzofuran-4-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (26) 10,11…”

“…We believe that designing potent uric acid transporter inhibitors may lead to novel therapeutic agents. Our previous works have described chemical synthesis and in vitro testing that produced important hURAT1 structure–activity relationship (SAR) data 10,11. As illustrated in Figure 1, we probed three different benzofuran templates (I, II, and III) and their ability to inhibit 14 C-urate uptake in oocytes expressing hURAT1.…”