Cystic fibrosis (CF) is a multi-organ disease of the lungs, sinuses, pancreas, and gastrointestinal tract, and is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator protein (CFTR), an epithelial anion channel that regulates salt and water balance in tissues and maintains homoeostasis of the airway surface liquid layer of the lungs. To address the most prevalent patient population (F508del mutation), two biomolecular modulators are required, namely correctors to increase properly folded CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Combined, these activities allow chloride ion transport leading to improved hydration of the lung surface and subsequent enhancement of mucociliary clearance. Abbvie and Galapagos are collaborating to develop a series of compounds capable of performing each of these activities individually.<br/><br/>In this presentation, we will disclose a new series of CFTR correctors with a tetrahydropyran scaffold. The synthesis effort and structure activity relationship (SAR) of these compounds will be described. These correctors became very useful tools to the understanding of CF biology.

Cystic fibrosis transmembrane conductance regulator protein (CFTR) correctors: Discovery and synthesis on THP series

255th National Meeting (2018)

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