Background:

Target: CFTR

IC50: 1.01 μM

IOWH-032 is a potent and synthetic extracellular cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor with IC50 value of 1.01 μM in T84 and CHO-CFTR cell based assays [1]. The CFTR chloride channel is the most attractive because it is the primary driver of secretion in cases of diarrhea caused by enterotoxigenic bacteria. CFTR plays an important role in transepithelial fluid homeostasis through controlling the flow of chloride ions and thus the movement of water in and out of cells [1].

In vitro: IOWH032 inhibited CFTR activity with IC50 value of 6.87 μM in T84-CFTR cell based assays [1]. IOWH-032 rapidly blocked and potentiated hCFTR activity in a concentration-dependent manner with apparent Kd value of 6.1 nM and 0.64 nM, respectively. However, IOWH-032 did not potentiate and only blocked mCFTR with an apparent Kd value of 42.9 μM [2].

In vivo: IOWH032 significantly inhibited cholera toxin (CTX)-induced secretion in a mouse closed-loop model. Moreover, IOWH032 (5 mg/kg, po dose) decreased the fecal output index by apparent 70% compared to vehicle (cholera toxin) in a cecetomized rat model. IOWH032 inhibited CFTR activity with IC50 value of 6.87 μM in T84-CFTR cell based assays [1].

参考文献:
1.  Doyle K, et al. Inhibitors Of The CFTR Chloride Ion Channel As Potential Treatment For Acute Secretory Diarrhea: Development Of 5-membered Heterocycles Suitable For Pre-clinical Evaluation.
1.  de Hostos EL, Choy RK, Nguyen T. Developing novel antisecretory drugs to treat infectious diarrhea. Future Med Chem. 2011;3(10):1317-25.
2.  Cui G, Khazanov N, Stauffer B, Infield DT, Imhoff BR, Senderowitz H, et al. Potentiators exert distinct effects on human, murine, and Xenopus CFTR. Am J Physiol Lung Cell Mol Physiol. 2016:ajplung 00056 2016.