CFTR potentiators

CFTR potentiator (F508del-CFTR Ka= 0.11 pM, G551D-CFTR Ka= 1.2 pM) with 250-fold selectivity over the L-type voltage-dependent Ca2+ channel [52,53],... 

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

Fluorescent-Based Assay Formats to Identify CFTR Potentiators... 

Potential Sites of Action for CFTR Potentiators Identified by HTS. Ill... 

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... 

Benzo[c]quinolizinium derivatives, like MPB-07 (compound 9), are reported to be potent potentiators of CFTR [41]. The effort started with the discovery that MPB-07 (compound 9) at concentrations >100 xM potentiated wild-type-CFTR, but not G551D-CFTR. SAR evaluation revealed that the hydroxyl at position 6 and the ammonium salt and a chlorine atom at positions 7 or 10 are essential for CFTR potentiation. In addition, addition of an alkyl chain at the 5 position, as in MPB-104 (compound 10), improved the potency 100 fold compared to MPB-07. These modifications also resulted in activity against G551D-CFTR, which was not observed for MPB-07. 

Fig. 7 Rescue of AF508-CFTR in HBE isolated from AF508-homozygous CF patients. A Representative short circuit current in AF508-HBE pre-treated for 48-hours with DMSO- (blue line) or 6.7 pM VRT-325 (red line). B Dose response to VRT-325 in FSK-stimulated AF508-HBE in the presence (filled circles) and absence (open circles) of the CFTR potentiator, VRT-532 (n = 5). C Maximum response to 10 iM FSK in AF508-HBE pre-treated with 1500 iM 4-PBA-, 6.7 iM VRT-422- (compoimd 1), 6.7 iM VRT-325-(compound 2), or 1 pM Corr-4a (compound 4), as well as 27°C-treated AF508-HBE. The peak response to forskolin was normalized to that in wild-type-HBE isolated from non-CF subjects (% wild-type CFTR). The dashed line indicates the level of residual (untreated) AF508-CFTR activity in AF508-HBE. D Cumulative data for uncorrected and VRT-325-corrected AF508-HBE with and without addition of the CFTR potentiator, VRT-532. Single asterisk = p<0.05 compared to un-treated controls double asterisk = p<0.01 compared to un-treated controls...

Ivacaftor (Kalydeco) A CFTR Potentiator for the Treatment of Cystic Fibrosis... 

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