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?F508-CFTR correctors: synthesis and evaluation of thiazole-tethered
imidazolones, oxazoles, oxadiazoles, and thiadiazoles
#MMPMID25452003
Ye L
; Hu B
; El-Badri F
; Hudson BM
; Phuan PW
; Verkman AS
; Tantillo DJ
; Kurth MJ
Bioorg Med Chem Lett
2014[Dec]; 24
(24
): 5840-5844
PMID25452003
show ga
The most common mutation causing cystic fibrosis (CF) is deletion of
phenylalanine residue 508 in the cystic fibrosis transmembrane regulator
conductance (CFTR) protein. Small molecules that are able to correct the
misfolding of defective ?F508-CFTR have considerable promise for therapy.
Reported here are the design, preparation, and evaluation of five more
hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1.
Interestingly, bisazole ?F508-CFTR corrector activity was not increased by
incorporation of more H-bond acceptors (O or N), but correlated best with the
overall bisazole molecular geometry. The structure activity data, together with
molecular modeling, suggested that active bisazole correctors adopt a U-shaped
conformation, and that corrector activity depends on the molecule's ability to
access this molecular geometry.
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