A critical analysis on ENaC inhibitors, unravelling molecular medicinal insights and promising research roadmap in the treatment of cystic fibrosis

Airway surface liquid (ASL) homeostasis is crucial for effective mucociliary clearance (MCC) and innate lung defense, both of which are severely compromised in cystic fibrosis (CF). Although CFTR modulators improved disease management, many patients remain ineligible due to mutations that cannot be targeted pharmacologically, highlighting the need for alternative therapeutic strategies. Among these, direct inhibition of the epithelial Na+ channel (ENaC) has emerged as a pharmacologically attractive approach to counteract airway dehydration. Due to adverse effects caused by systemic ENaC inhibition, and in particular related to potassium homeostasis, medicinal chemistry efforts have focused on inhaled, lung-restricted inhibitors. This review examines the evolution of direct ENaC blockers from early amiloride-like compounds to more advanced clinical candidates, emphasizing the medicinal chemistry principles that enabled improved airway selectivity. In particular, the optimization process progressively shifted to a multi-parameter strategy integrating persistent positive charge, increased polarity, reduced lipophilicity and low epithelial permeability, in order to decrease pulmonary absorption, prolong lung retention and reduce systemic exposure. In this context, special attention is given to positively charged acylguanidine mimetics, including quaternary amines and N-alkylated benzimidazoles. Overall, the field shows that for inhaled ENaC inhibitors, therapeutic success depends not only on nanomolar target potency, but on achieving sustained local airway exposure with minimal renal liability.