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

Abstract

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.