High potency 3-carboxy-2-methylbenzofuran pendrin inhibitors as novel diuretics

Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC₅₀ ∼10 μM). Here, we performed a de novo small molecule screen with follow-on structure-activity studies to identify more potent pendrin inhibitors. Screening of 50,000 synthetic small molecules identified four novel classes of pendrin inhibitors with diverse scaffolds, including 5-benzyloxy-2-methylbenzofurans, N-aryl urea substituted 5-methyltryptamines, N-aryl urea substituted anthranilic acids, and substituted N-benzyl 3-carboxyindoles. The most potent inhibitor from the initial screen, a 3-carboxy-2-methylbenzofuran (1a), had IC₅₀ of 4.1 μM. Structure-activity studies using 732 benzofuran analogs identified 1d with IC₅₀ ∼ 0.5 μM for pendrin inhibition. Selectivity studies showed that 1d has minimal or no activity against related ion channels/transporters including SLC26A3, SLC26A6 and CFTR at high concentrations. 1d administration to mice at 10 mg/kg had no effect on urine volume when used alone, but potentiated the diuretic effect of furosemide by 45 %. In conclusion, we have identified novel pendrin inhibitors with greatly improved potency and good in vivo efficacy. These compounds can be used as pharmacological tools to study the roles of pendrin, and potentially developed as drug candidates for edema, hypertension and lung diseases.