Ligand-based design, in silico ADME-Tox filtering, synthesis and biological evaluation to discover new soluble 1,4-DHP-based CFTR activators

The altered gating of the mutant CFTR chloride channel cystic fibrosis (CF) may be corrected by small molecules called potentiators. We present a molecular scale simulation system for the discovery of ΔF508-CFTR soluble potentiators. Results report the design, ADME-Tox prediction, synthesis, solubility determination and in vitro biological evaluation of two 1,4-dihydropyridines (DHPs). Compound 1 shows a promising ADME–Tox profile and good potency.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The feasibility of producing water soluble, potent and selective CFTR potentiators with the 1,4-DHP scaffold was checked. ► Two GRIND based 3D-QSAR models to predict CFTR activation and l-VDCC block were built. ► Two 1,4-DHPs of potential interest were synthetized and experimentally tested.