Property-driven design yields inhaled sGC stimulator frespaciguat for PH-COPD
- Oral sGC stimulators can cause systemic hypotension and worsen ventilation-perfusion mismatch in PH-COPD, motivating a lung-restricted design.
- SAR and PK work identified high systemic clearance and low permeability as the key drivers of pulmonary selectivity.
- Compound 15 (frespaciguat, MK-5475) is a very potent stimulator with long target residence time and more than 200-fold unbound lung-to-plasma exposure after inhalation, with efficacy in a rat chronic hypoxia model.
💡 Points
Designing for high clearance and low permeability on purpose is the opposite of oral-drug instinct, which is exactly why this paper is useful for inhaled programs. Residence time plus lung retention is the combination I'd want to see replicated before believing the therapeutic window in humans.