Optimisation of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis

Abstract

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimisation of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13 % of the delivered dose retained after 6h) following intratracheal administration and a potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED₁₀₀ (4-6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.

Keywords: Benzimidazolium; Cystic fibrosis; ENaC inhibitor; Inhalation; Low permeability; Mucocilliary clearance.