{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:12:17Z","timestamp":1793409137338,"version":"4.5.0"},"reference-count":48,"publisher":"American Society for Clinical Investigation","issue":"14","funder":[{"name":"NIDDK, NEI, Cystic Fibrosis Foundation, Cystic Fibrosis Research Inc.","award":["DK099803,DK72517,DK101373,EY13573,CFF,R613,CFRI New Horizons"],"award-info":[{"award-number":["DK099803,DK72517,DK101373,EY13573,CFF,R613,CFRI New Horizons"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,26]]},"abstract":"<jats:p>\n                    SLC26A3 (downregulated in adenoma; DRA) is a Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    \/anion exchanger expressed in the luminal membrane of intestinal epithelial cells, where it facilitates electroneutral NaCl absorption. SLC26A3 loss of function in humans or mice causes chloride-losing diarrhea. Here, we identified slc26a3 inhibitors in a screen of 50,000 synthetic small molecules done in Fischer rat thyroid (FRT) cells coexpressing slc26a3 and a genetically encoded halide sensor. Structure-activity relationship studies were done on the most potent inhibitor classes identified in the screen: 4,8-dimethylcoumarins and acetamide-thioimidazoles. The dimethylcoumarin DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A250 fully and reversibly inhibited slc26a3-mediated Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    exchange with HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2013<\/jats:sup>\n                    , I\n                    <jats:sup>\u2013<\/jats:sup>\n                    , and thiocyanate (SCN\n                    <jats:sup>\u2013<\/jats:sup>\n                    ), with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of ~0.2 \u03bcM. DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A250 did not inhibit the homologous anion exchangers slc26a4 (pendrin) or slc26a6 (PAT-1), nor did it alter activity of other related proteins or intestinal ion channels. In mice, intraluminal DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A250 blocked fluid absorption in closed colonic loops but not in jejunal loops, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum. Oral DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A250 and tenapanor comparably reduced signs of constipation in loperamide-treated mice, with additive effects found on coadministration. DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A250 was also effective in loperamide-treated cystic fibrosis mice. These studies support a major role of slc26a3 in colonic fluid absorption and suggest the therapeutic utility of SLC26A3 inhibition in constipation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.121370","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T11:01:04Z","timestamp":1532516464000},"source":"Crossref","is-referenced-by-count":53,"title":["SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation"],"prefix":"10.1172","volume":"3","author":[{"given":"Peter M.","family":"Haggie","sequence":"first","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onur","family":"Cil","sequence":"additional","affiliation":[{"name":"Department of Medicine,"},{"name":"Department of Pediatrics, 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