molecules of the month

The Novartis mutant and WT CFTR potentiator, icenticaftor (QBW251), is an oral Ph. II clinical candidate for chronic obstructive pulmonary disease (COPD), which is anticipated to become the 3rd leading cause of death globally. The compound had positive proof of concept studies in both cystic fibrosis and COPD, and the advancement of a WT CFTR modulator into the large COPD indication is a significant development. Since there are not good PK/PD models for cystic fibrosis, the candidate was nominated based on in vitro properties and safety studies, but has shown target engagement in humans via biomarkers such as sweat chloride. This is a great medicinal chemistry case study as the starting point for icenticaftor was objectively unattractive, with furan, aniline, and ester…