Cyclic diacyl thioureas enhance activity of corrector Lumacaftor on F508del‐CFTR

• Published in: ChemMedChem 2024-02, Vol.19 (4), p.e202300391-n/a
• Main Authors: Spallarossa, Andrea, Pedemonte, Nicoletta, Pesce, Emanuela, Millo, Enrico, Cichero, Elena, Rosano, Camillo, Lusardi, Matteo, Iervasi, Erika, Ponassi, Marco
• Format: Article
• Language: English
• Subjects: Acylthioureas; CFTR modulator; Conductance; Cystic fibrosis; cytotoxic activity; Cytotoxicity; Genetic disorders; Modulators; Pharmacokinetics; Thioureas; Tumor cell lines
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300391

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del‐CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6 i displayed the most marked enhancing effect and acylthioureas 6 d and 6 f were also able to improve efficacy of Lumacaftor. All compounds proved to be non‐cytotoxic against different cancer cell lines. Good pharmacokinetic properties were predicted for derivatives 5 and 6, thus supporting the value of these compounds for the development of novel modulators potentially useful for cystic fibrosis. A series of mono‐ and di‐acylthioureas was synthesised and tested as CFTR modulators. Despite the lack of any intrinsic potentiating effect, selected compounds enhanced the rescue activity of Lumacaftor, as observed in phenotypic assays. The lack of cytotoxic effects and the promising pharmacokinetic properties support the pharmacological relevance of this class of compounds as novel hits for cystic fibrosis treatment.