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
| Autor: | Luis J. V. Galietta, Salvatore La Rosa, Nicoletta Pedemonte, Laura Maccari, Laura Bettinetti, Letizia Magnoni, Paola Fanti, Elisabetta Pesci, Gian Luca Sardone |
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| Přispěvatelé: | Pesci, Elisabetta, Bettinetti, Laura, Fanti, Paola, Galietta, Luis J. V., La Rosa, Salvatore, Magnoni, Letizia, Pedemonte, Nicoletta, Sardone, Gian Luca, Maccari, Laura |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cell Membrane Permeability
Cystic Fibrosis Pyridines Pyridine Cell Cystic Fibrosis Transmembrane Conductance Regulator Respiratory Mucosa Pharmacology medicine.disease_cause Cystic fibrosis Cell Line Structure-Activity Relationship Dogs Drug Discovery medicine Protein biosynthesis Dog Structure–activity relationship Animals Humans ΔF508 Cystic Fibrosi ADME Mutation biology Chemistry Animal Drug Discovery3003 Pharmaceutical Science Membranes Artificial medicine.disease Cystic fibrosis transmembrane conductance regulator medicine.anatomical_structure Pyrimidines Pyrimidine Solubility biology.protein Microsomes Liver Molecular Medicine Human |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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