Identification of 6,9-dihydro-5H-pyrrolo[3,2-h]quinazolines as a new class of F508del-CFTR correctors for the treatment of cystic fibrosis.

ABSTRACT

Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445. From the exploration of the chemical space around the hit structure, based on iterative cycles of chemical synthesis and functional testing, the class of 6,9-dihydro-5H-pyrrolo [3,2-h]quinazolines with corrector activity was discovered. Within a series of 38 analogues, two derivatives emerged as promising candidates and used for further insight to assess the mechanism of action. Both compounds, decorated with a benzensulfonylamino group at the pyrimidine moiety, were able to generate a dose-dependent increase in CFTR function, particularly in the presence of VX-809. Half-effective concentrations (EC50) were in the single digit micromolar range and decreased in the presence of VX-809 thus indicating a synergistic interaction with class 1 correctors. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF.