Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disorder in Caucasian populations, affecting approximately 70,000 patients worldwide. It is caused by mutations of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This results in a decreased chloride transport across epithelial tissues. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Combined, these activities allow chloride ion transport, yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. We are developing compounds capable of performing both these activities individually, and we report here the identification of novel potentiators able to open the CFTR channel with high efficacy.<br/>An initial screen was performed to identify compounds that modulate CFTR protein activity located at the cell surface, leading to enhanced chloride transport. A set of 589 compounds, selected using 2D structural/electrostatic field similarities to known potentiator compounds were screened. Hit expansion around the most active hits resulted in the discovery of a novel series that showed enhanced channel opening when compared to the disease modifying agent Kalydeco on G551D CFTR. Further medicinal chemistry efforts focused on improving efficacy, ADME and PK, but also the overall drug-drug interaction profile. This resulted in the identification and development of GLPG1837, a novel potentiator that shows enhanced efficacy in primary human bronchial epithelium cells (HBE) derived from CF patients. At the time of submitting this abstract, GLPG1837 is undergoing Phase 2trials in CF patients with class III mutations.

Discovery of highly efficacious potentiators for the treatment of cystic fibrosis

253rd National Meeting (2017)

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