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'. 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. Following this structural indication, we synthesized a small set of new molecules endowed with a significant, even if not great, F508del-CFTR rescue activity. 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
The search for a common structural moiety among selected pharmacological correctors of the mutant CFTR chloride channel.
POLLAROLO, BENEDETTA;SCHENONE, SILVIA;MAZZEI, MAURO
2014-01-01
Abstract
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'. 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. Following this structural indication, we synthesized a small set of new molecules endowed with a significant, even if not great, F508del-CFTR rescue activity. 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 designI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.