title: Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3-d]pyrimidines for the Potential Treatment of Cystic Fibrosis.
abstract: Cystic fibrosis (CF) is a lethal genetic disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) with a prevalence of the ΔF508 mutation. Whereas the detailed mechanisms underlying disease have yet to be fully elucidated, recent breakthroughs in clinical trials have demonstrated that CFTR dysfunction can be corrected by drug-like molecules. On the basis of this success, a screening campaign was carried out, seeking new drug-like compounds able to rescue ΔF508-CFTR that led to the discovery of a novel series of correctors based on a tetrahydropyrido[4,3-d]pyrimidine core. These molecules proved to be soluble, cell-permeable, and active in a disease relevant functional-assay. The series was then further optimized with emphasis on biological data from multiple cell systems while keeping physicochemical properties under strict control. The pharmacological and ADME profile of this corrector series hold promise for the development of more efficacious compounds to be explored for therapeutic use in CF.
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pesci
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bettinetti
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fanti
authors.affiliation: Istituto Giovannina Gaslini , Genova 16148, Italy.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.affiliation: Istituto Giovannina Gaslini , Genova 16148, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Sardone
authors.affiliation: Siena Biotech S.p.A. , Strada del Petriccio e Belriguardo 35, Siena 53100, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maccari
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D003550:Cystic Fibrosis / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008567:Membranes, Artificial; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008567:Membranes, Artificial; D011725:Pyridines; D011743:Pyrimidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator