The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, belonging to the ABC family of transporters, lies at the heart of hypersecretion associated with AWD (acute watery diarrhea) caused by enterotoxigenic bacteria. IOWH032, chloride channel blocker, is a synthetic CFTR inhibitor with antisecretory activity developed by OneWorld Health and currently in Phase I clinical trials to treat diarrhea[3]. During a ~50s extracellular exposure to 5 nM IOWH-032, hCFTR was blocked. Specificly, IOWH-032 blocked hCFTR rapidly in a concentration-dependent manner with apparent Kd of 6.1 nM. Through time, it also potentiated hCFTR in a concentration-dependent manner with an apparent Kd of 0.64 nM. Moreover, 20 nM IOWH-032 potentiated F508del-hCFTR expressed in Xenopus oocytes[4]. In two animal models of secretory diarrhea, injection of iOWH032 directly into intestinal loops inhibited secretion by nearly 70% as measured on a semi-quantitative fecal output scale[3].
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