Novel Macrocyclic 1,3,4-Oxadiazoles as CFTR Modulators for Treating Cystic Fibrosis

Abstract

Assignee Company. Vertex Pharmaceuticals Incorporated, USA Disease Area. Cystic fibrosis Biological Target. CFTR Summary. Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 83 000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure. In patients with CF, mutations in cystic fibrosis transmembrane conductance regulator (CFTR), endogenously expressed in respiratory epithelia, lead to reduced apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with CF are infertile, and fertility is reduced among females with CF.Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations. To date, more than 2000 mutations in the CF gene have been identified. Currently, the CFTR2 database contains information on only 322 of these