azd5634

AZD5634 is a novel, potent small molecule inhibitor of the epithelial sodium channel (ENaC), developed for inhaled administration. It exhibits high affinity for ENaC in human, sheep, and rat airway cells (IC50 of 3.8 nmol/L in humans) and is designed to restore airway surface liquid (ASL) depth and enhance mucociliary clearance (MCC), particularly in cystic fibrosis (CF). Unlike earlier ENaC inhibitors such as amiloride, AZD5634 demonstrates extended lung retention with minimal systemic absorption and does not cause hyperkalemia due to low renal clearance. Preclinical studies show that AZD5634 increases ASL volume and improves mucociliary transport rates in vitro; however, clinical trials have not yet demonstrated significant improvement in MCC or airway hydration after single-dose inhalation in CF patients or animal models. The drug may also inhibit sodium/hydrogen exchangers, potentially aiding mucus detachment. Developed by AstraZeneca, AZD5634 has completed Phase 1 clinical trials for cystic fibrosis and pulmonary fibrosis but has not advanced beyond this stage as of April 2025.