Novel picolinamide-based cystic fibrosis transmembrane regulator modulators: evaluation of WO2013038373, WO2013038376, WO2013038381, WO2013038386 and WO2013038390.

Cystic fibrosis (CF) is a genetic disease caused by defects in the CF transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel. The most common mutation, Δ508CFTR, produces a protein that is misfolded and does not reach the cell membrane. The discovery that partial chloride channel function could be restored by exposure to exogenous chemical stimuli led to the search for selective CFTR modulators. Vertex has led the way in developing N-aryl-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide derivatives such as lumacaftor and VX-661, which correct trafficking of Δ508CFTR and partially restore chloride channel activity. Novartis had identified similar activity in a series of picolinamide derivatives such as 3-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide. A series of five filings from Novartis has expanded on the activity of compounds based on this scaffold and provided compounds with nanomolar potency in cellular assays.