Issue 5, 2024

Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria

Abstract

SLC26A3, also known as downregulated in adenoma (DRA), is an anion (Cl, HCO3 and oxalate) exchanger in the luminal membrane of intestinal epithelial cells. Loss of DRA function in mice and humans causes congenital chloride-losing diarrhea and reduces urinary excretion of oxalate, a major constituent of kidney stones. Thus, inhibition of DRA is a potential treatment approach for constipation and calcium oxalate kidney stones. High-throughput screening previously identified 4,8-dimethylcoumarins (4a–4c) as DRA inhibitors, with lead candidate 4b having an IC50 of 40–50 nM for DRA inhibition. Here, we explored the effects of varying substituents at the 8-position, and replacing 8-methyl by 5-methyl (4e–4h). A focused library of 17 substituted compounds (4d–4t) was synthesized with good yield and purity. Compounds were tested for DRA inhibition potency using Fischer rat thyroid cells stably expressing DRA and a halide-sensitive YFP. Structure–activity analysis revealed that 8-bromo- (4m–4p) and 8-fluoro-coumarins (4q–4t) were slightly less potent than the corresponding 8-chloro analogs, demonstrating that the size of methyl or chloro substituents at the coumarin 8 position affects the potency. An analog containing 8-chlorocoumarin (4k) had ∼2-fold improved potency (IC50 25 nM) compared with the original lead candidate 4b. 5,8-Dimethylcoumarins were active against DRA, but with much lower potency than 4,8-disubstituted coumarins. In mice, orally administered 4k at 10 mg kg−1 reduced constipation and normalized stool water content in a loperamide-induced constipation model with comparable efficacy to 4b. Pharmacokinetic analysis of orally administered 4k at 10 mg kg−1 in mice indicated serum levels of >10 μM for at least six hours after single dose. This study expands SAR knowledge of 4,8-disubstituted coumarin inhibitors of DRA as novel drug candidates for constipation and kidney stones.

Graphical abstract: Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria

Supplementary files

Article information

Article type
Research Article
Submitted
17 Nov 2023
Accepted
27 Feb 2024
First published
09 Apr 2024

RSC Med. Chem., 2024,15, 1731-1736

Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria

M. Ahmadi, L. de Souza Goncalves, A. S. Verkman, O. Cil and M. O. Anderson, RSC Med. Chem., 2024, 15, 1731 DOI: 10.1039/D3MD00644A

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