Small molecule inhibitors of intestinal epithelial anion exchanger SLC26A3 (DRA) with a luminal, extracellular site of action

• Published in: European journal of medicinal chemistry 2023-03, Vol.249, p.115149-115149, Article 115149
• Main Authors: Cil, Onur, Anderson, Marc O., de Souza Goncalves, Livia, Tan, Joseph-Anthony, Haggie, Peter M., Verkman, Alan S.
• Format: Article
• Language: English
• Subjects: Animals; Anions; Antiporters - chemistry; Antiporters - metabolism; Antiporters - pharmacology; Biological Transport; Chlorides - metabolism; Constipation; Down-regulated in adenoma; Kidney stones; Mice; Molecular Docking Simulation; Non-absorbable drugs; SLC26; Sulfate Transporters - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115149

The anion exchanger protein SLC26A3 (down-regulated in adenoma, DRA) is expressed in the luminal membrane of intestinal epithelial cells in colon, where it facilitates the absorption of Cl− and oxalate. We previously identified a 4,8-dimethylcoumarin class of SLC26A3 inhibitors that act from the SLC26A3 cytoplasmic surface, and demonstrated their efficacy in mouse models of constipation and hyperoxaluria. Here, screening of 50,000 new compounds and 1740 chemical analogs of active compounds from the primary screen produced five novel classes of SLC26A3-selective inhibitors (1,3-dioxoisoindoline-amides; N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamides; thiazolo-pyrimidin-5-ones; 3-carboxy-2-phenylbenzofurans and benzoxazin-4-ones) with IC50 down to 100 nM. Kinetic washout and onset of action studies revealed an extracellular site of action for the thiazolo-pyrimidin-5-one and 3-carboxy-2-phenylbenzofuran inhibitors. Molecular docking computations revealed putative binding sites for these inhibitors. In a loperamide model of constipation in mice, orally administered 7-(2-chloro-phenoxymethyl)-3-phenyl-thiazolo [3,2-a]pyrimidin-5-one (3a) significantly increased stool weight, pellet number and water content. SLC26A3 inhibitors with an extracellular site of action offer the possibility of creating non-absorbable, luminally acting inhibitors with minimal systemic exposure following oral administration. Our findings also suggest that inhibitors of related SLC26 anion transporters with an extracellular site of action might be identified for pharmacological modulation of selected epithelial ion transport processes. [Display omitted] •Constipation and kidney stones are very common problems.•SLC26A3 anion transporter is a target for constipation and kidney stone treatment.•SLC26A3 inhibitors with luminal site of action have been identified.•Non-absorbable SLC26A3 inhibitors can have minimal systemic toxicity.