4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger slc26a3 (Downregulated in Adenoma) for Anti-Absorptive Therapy of Constipation.
Lee S, Cil O, Haggie PM, Verkman AS.
The chloride/bicarbonate exchanger SLC26A3 (downregulated in adenoma) is expressed mainly in colonic epithelium, where it dehydrates the stool by facilitating the final step of chloride and fluid absorption. SLC26A3 inhibition has predicted efficacy in various types of constipation including that associated with cystic fibrosis. We previously identified, by high-throughput screening, 4,8-dimethylcoumarin inhibitors of murine slc26a3 with IC<sub>50</sub> down to ∼150 nM. Here, we synthesized a focused library of forty-three 4,8-dimethylcoumarin analogues. Structure-activity studies revealed the requirement of 4,8-dimethylcoumarin-3-acetic acid for activity. The most potent inhibitors were produced by replacements at C7, including 3-iodo- (<b>4az</b>) and 3-trifluoromethyl- (<b>4be</b>), with IC<sub>50</sub> of 40 and 25 nM, respectively. Pharmacokinetics in mice showed predicted therapeutic concentrations of <b>4az</b> for >72 h following a single 10 mg/kg oral dose. <b>4az</b> at 10 mg/kg fully normalized stool water content in a loperamide-induced mouse model of constipation. The favorable inhibition potency, selectivity within the SLC26 family, and pharmacological properties of <b>4az</b> support its further preclinical development.