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 (IC ∼10 μM).

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.

A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine).

Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells.

Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl- secretion in human intestinal epithelial T84 cells.