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

Elisabetta Pesci, Laura Bettinetti, Paola Fanti, Luis J V Galietta, Salvatore La Rosa, Letizia Magnoni, Nicoletta Pedemonte, Gian Luca Sardone, Laura Maccari

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9697-9711
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number24
DOIs
Publication statusPublished - Dec 24 2015

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Cystic Fibrosis Transmembrane Conductance Regulator
Pyrimidines
Cystic Fibrosis
Pharmacology
Mutation
Inborn Genetic Diseases
Proteins
Therapeutic Uses
Pharmaceutical Preparations
Clinical Trials
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Pesci, Elisabetta; Bettinetti, Laura; Fanti, Paola; Galietta, Luis J V; La Rosa, Salvatore; Magnoni, Letizia; Pedemonte, Nicoletta; Sardone, Gian Luca; Maccari, Laura.

In: Journal of Medicinal Chemistry, Vol. 58, No. 24, 24.12.2015, p. 9697-9711.

Research output: Contribution to journalArticle

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