Description
IOWH032 is a synthetic CFTR inhibitor with IC50 of 1.01 μM in CHO-CFTR cell based assays. Phase 2.
In vitro
IOWH032 shows inhibitory activity against CFTR in T84-CFTR cell based assays with IC50 of 6.87 μM.
In vivo
In a mouse closed-loop model, IOWH032 causes a statistical significant inhibition against cholera toxin (CTX) induced secretion. IOWH032 (5 mg/kg) reduces the fecal output index by ~70% in a cecetomized rat model.
Uses
IOWH032 is a synthetic?cystic fibrosis transmembrane conductance regulator (CFTR) ?inhibitor.
Biological Activity
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].
References
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.
