Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Mutations in the cystic fibrosis
transmembrane conductance regulator
(CFTR) ion channel are established as the primary causative factor
in the devastating lung disease cystic fibrosis (CF). More recently,
cigarette smoke exposure has been shown to be associated with dysfunctional
airway epithelial ion transport, suggesting a role for CFTR in the
pathogenesis of chronic obstructive pulmonary disease (COPD). Here,
the identification and characterization of a high throughput screening
hit 6 as a potentiator of mutant human F508del and wild-type
CFTR channels is reported. The design, synthesis, and biological evaluation
of compounds 7–33 to establish structure–activity
relationships of the scaffold are described, leading to the identification
of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical
proofs of concept in patients with CF and COPD and is now being further
developed as a novel therapeutic approach for COPD patients.