Soluble guanylate cyclase (sGC) stimulators are a validated therapeutic approach for pulmonary vasodilation; however, oral agents can cause systemic hypotension and may worsen ventilation-perfusion mismatch in pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). To address these limitations, we applied a property-driven medicinal chemistry strategy to develop an inhaled sGC stimulator that maximizes pulmonary exposure while minimizing systemic exposure. Structure-activity relationship and pharmacokinetic studies identified high systemic clearance and low permeability as key determinants of pulmonary selectivity. These insights led to the discovery of compound 15 (frespaciguat, MK-5475), a subnanomolar sGC stimulator with a prolonged target residence time and >200-fold unbound lung-to-plasma exposure following inhalation. In a rat chronic hypoxia-induced PH model, frespaciguat produced dose-dependent reductions in pulmonary arterial pressure with minimal systemic hemodynamic effects and pharmacodynamic activity persisting >24 h after a single dose. These findings and early clinical data support the development of frespaciguat as an inhaled pulmonary-selective sGC stimulator for PH-COPD.