A property-driven medicinal chemistry strategy produced frespaciguat (MK-5475, compound 15), an inhaled sGC stimulator with subnanomolar potency and >200-fold unbound lung-to-plasma exposure, which lowered pulmonary arterial pressure in a rat chronic hypoxia PH model with minimal systemic hemodynamic effects, supporting its development for PH-COPD.
Structure-activity relationship and pharmacokinetic studies identified high systemic clearance and low permeability as key determinants of pulmonary selectivity for inhaled sGC stimulators.
Frespaciguat (compound 15, MK-5475) is a subnanomolar sGC stimulator with a prolonged target residence time.
Following inhalation, frespaciguat showed greater than 200-fold unbound lung-to-plasma exposure.
In a rat chronic hypoxia-induced PH model, frespaciguat produced dose-dependent reductions in pulmonary arterial pressure with minimal systemic hemodynamic effects.
Pharmacodynamic activity of frespaciguat persisted for more than 24 hours after a single dose in the rat model.
The preclinical findings and early clinical data support development of frespaciguat as an inhaled pulmonary-selective sGC stimulator for PH-COPD.
Pulmonary hypertension (high blood pressure in the lung arteries) is a serious complication in people with COPD. Drugs called sGC stimulators can relax lung blood vessels, but when taken by mouth they spread through the whole body, which can lower overall blood pressure and may worsen the match between airflow and blood flow in the lungs. This study describes the design of an inhaled version intended to stay mostly in the lungs. The researchers found that drugs cleared quickly from the bloodstream and poorly absorbed across membranes were more likely to stay concentrated in the lung. Using these rules, they developed frespaciguat (MK-5475), a very potent compound that binds its target for a long time. After inhalation, the amount of unbound drug in the lung was over 200 times that in the blood plasma. In rats with pulmonary hypertension induced by chronic low oxygen, frespaciguat lowered pulmonary artery pressure in a dose-dependent way with little effect on systemic blood pressure, and its effects lasted over 24 hours after one dose. This research suggests the approach could work as a lung-targeted treatment for PH-COPD, and the authors note early clinical data support further development. The abstract does not report detailed human results, so it remains to be shown in larger clinical studies whether the benefits seen in rats translate to patients.
Whitehead A, Berger R, Zhang Y, Ornoski O, Kim H, Cox J, et al.. (2026). Frespaciguat (MK-5475): A Novel Inhaled Soluble Guanylate Cyclase Stimulator for Pulmonary Hypertension Associated with COPD.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c01683