CFTR correctors

One promising approach to identify novel CFTR corrector structural classes is to screen compounds, already developed for other indications, for their ability to correct the trafficking defect of mutant CFTR. Following this approach, glafenine hydrochloride (17), miglustat (18), and SAHA (19) were recently described as promising CFTR corrector leads. 

Administration of 17 to homozygous F508del-CFTR mice for 48 h, using a micro-osmotic pump delivery system (50 ig/h), increased the salivary secretion to 6.6% of normal wild-type control mice. Compound 18, an inhibitor of the a-1,2 glucosidase, was reported as a CFTR corrector... 

Two approaches have been taken to identify CFTR modulators with both CFTR potentiator and CFTR corrector activities in a single molecule. One... 

Because mutant CFTR is the core defect in CF, it is expected that pharmacological agents designed to increase CFTR function will prevent or slow disease progression (Fig. 1). There are two pharmacological approaches to increase mutant CFTR function. The first is to increase the cell surface density of mutant CFTR. This class of compounds is known as CFTR correctors (Fig. 2B). The second approach is to increase the open probability of mutant CFTR at the cell surface. This class of compounds is known as CFTR potentiators (Fig. 2B). Depending on the molecular consequence of the mutation... 

Davison, H. R. Taylor, S. Drake, C. Phuan, P Derichs, N. Yao, C. Jones, E. R Sutcliffe, J. Verkman, A. S. Kurth, M. J. Eunctional fluorescently labeled bithiazole AE508-CFTR corrector imaged in whole body slices in mice. Bioconjugate Chem. 2011, 22,2593-2599. 

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