Ctg-21-0250 1..4

INTRODUCTION Guanylyl cyclase C (GCC) is a receptor enzyme in the apical membrane of enterocytes. Its extracellular receptor domain binds guanylin, uroguanylin, the heat-stable Escherichia coli enterotoxin heat stable enterotoxin (ST) (1–3), and the synthetic peptide linaclotide (4). GCC ligand binding increases the intracellular cyclic guanosine monophosphate (cGMP) level, which triggers protein kinase–mediated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and inhibition of the sodium-proton exchanger NHE3. This dual action promotes the retention of salt and water in the gut lumen (2,5), and abnormally high GCC activity leads to diarrhea. One type of congenital enteropathy, the classical form of congenital sodium diarrhea (CSD), is caused by gain-of-function mutations in GUCY2C, encoding GCC (6–8), or by loss-offunction mutations in NHE3 (9). Such GCC mutations result in polyhydramnios and severe diarrhea from birth onward, generally requiring long-term parenteral nutrition (PN) (7). Given the severe complications of long-term PN, new treatment options are warranted. Two different types of specific GCC inhibitors were developed so far, an N-2-(propylamino)-6-phenylpyrimidin-4one–substituted piperidine (SSP2518) (10) and a pyridopyrimidine derivative (BPIPP) (11).