CFTR inhibitors for treating diarrheal disease

Abstract

Secretory diarrhea remains a major health challenge worldwide. Excessive fluid secretion in the intestine caused by enterotoxins results in activation of luminal Cl- channels on enterocytes. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the major cyclic adenosine monophosphate (cAMP)-regulated Cl- channel activated in cholera as well as in diarrheas caused by other bacterial enterotoxins. Small-molecule screens have yielded CFTR inhibitors with half-maximal inhibitory concentration (IC50) values as low as 4 nmol/l. The data from proof-of-concept studies in animal models support the development of CFTR inhibitors for antidiarrheal therapy.

Figure 1

Intestinal fluid transporting mechanisms. Lower left: crypt–villus unit in the small intestine, comprising basal crypt stem cells, enterocytes, enterochromaffin cells (EC cells), and goblet cells. Right: crypt secretory cell with luminal (top) and basal (bottom) transporters, ion channels, and second messengers. Left: villus absorptive cell with luminal (top) and basal (bottom) transporters. cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CaCC, Ca²⁺-activated Cl⁻ channel; CFTR, cystic fibrosis transmembrane conductance regulator; STa, heat-stable.

Figure 2

Chemical structures of small-molecule CFTR inhibitors. Top: original (pre-high–throughput screening) CFTR inhibitors. Center: absorbable CFTR inhibitors acting at the CFTR cytoplasmic surface. Bottom: externally acting hydrazide-class CFTR inhibitors. BPO, benzopyrimido-pyrrolo-oxazine-dione; CFTR, cystic fibrosis transmembrane conductance regulator; DPC, diphenylamine-2-carboxylate; NPPB, 5-nitro-2-(3-phenylpropyl-amino)benzoate; PPQ, pyrimido-pyrrolo-quinoxalinedione.