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.
CASSMedChem Research Group, DSTF at the Centre for Innovation, Università di Torino, Via Quarello 11, 10135 Torino, Italy.
Sonja
S
Visentin
Giuseppe
G
Ermondi
Claudio
C
Medana
Nicoletta
N
Pedemonte
Luis
L
Galietta
Giulia
G
Caron
D000042:Absorption; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D060326:Chemistry Techniques, Synthetic; D019295:Computational Biology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012995:Solubility
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008024:Ligands; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C038806:1,4-dihydropyridine