The search for a common structural moiety among selected pharmacological correctors of the mutant CFTR chloride channel.

Abstract:

BACKGROUND:The F508del mutation impairs the trafficking of CFTR from endoplasmic reticulum to plasma membrane and is responsible of a severe form of cystic fibrosis. Trafficking can be improved by small organic molecules called 'correctors'. MATERIALS & METHODS:By different synthetic ways, we prepared 4-chloroanisole and 2-(4-chloroanisol-2-yl)aminothiazole derivatives. Such compounds were ineffective as correctors but we could find a sign of activity in an intermediate. In the meantime, we found a common pharmacophoric moiety present in four known correctors. RESULTS:Following this structural indication, we synthesized a small set of new molecules endowed with a significant, even if not great, F508del-CFTR rescue activity. CONCLUSION:The cited structural feature seems interesting in the search of new correctors. To corroborate this observation, later on we found a new pyrazine derivative (Novartis) endowed with a potent activity as corrector and having the cited common design.

journal_name

Future Med Chem

authors

Nieddu E,Pollarolo B,Mazzei MT,Anzaldi M,Schenone S,Pedemonte N,Pesce E,Galietta LJ,Mazzei M

doi

10.4155/fmc.14.118

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

1857-68

issue

17

eissn

1756-8919

issn

1756-8927

journal_volume

6

pub_type

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