Inhalation of a small molecule known as PK10453, formally known as (R-phenyl)pyrazin-R-methylnicotinamide, prevented pulmonary arterial hypertension progression in rats who were predisposed for developing pulmonary hypertension. Researchers under the leadership of Dr. Lawrence Zisman at Bassett Medical Center and other institutes in New York and Minnesota published their new findings in Pulmonary Circulation.
PK10453 was effective in preventing pulmonary hypertension due to its involvement in the platelet-derived growth factor (PDGF) signaling pathway, which is activated in both human idiopathic and animal pulmonary arterial hypertension. Previous studies have delved into the PDGF pathway for pulmonary hypertension treatment: imatinib (a PDGF receptor inhibitor) has been found to decrease right ventricular systolic pressure in rats and improve six-minute walk distance in humans.
In the study at hand, rat monocrotaline models with and without pneumonectomy were subjected to inhaling PK10453 for either four or eight minutes three times a day for two weeks. After this period, the investigators found reduced right ventricular systolic pressure compared to rats that were not treated with PK10453. Further, continuous telemetry monitoring of pulmonary artery pressure revealed PK10453 prevented disease progression in the rats with pneumonectomy.
The authors reasoned that PK10453 is successful for preventing pulmonary hypertension because it inhibits both PDGFα and PDGFβ receptors–imatinib inhibits only the PDGFα receptor. What’s more, PK10453 has a lower half-maximal inhibitor concentration (IC50) than imatinib.
A lower concentration of drug required to demonstrate an effect is valuable for treatment options. Although these experiments are preliminary, if they were to translate into human studies, it may be shown PK10453 is more effective than imatinib in treating pulmonary arterial hypertension.