PAH treatment CPD1 shows promise in preclinical study
Rat experiments show new inhibitor reduces disease severity
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Scientists in China have developed a phosphodiesterase-5 (PDE5) inhibitor for pulmonary arterial hypertension (PAH) that reduced disease severity in a rat model of PAH.
The scientists detailed the development and testing of the treatment, CPD1, in a study that also shed light on the molecular mechanisms through which the new therapy exerts its effects, setting it apart from conventional PDE5 inhibitors currently approved for PAH.
“This study provides comprehensive preclinical evidence that the novel PDE5 inhibitor CPD1 is a potent therapeutic candidate for PAH,” the researchers wrote.
The study, “The novel PDE5 inhibitor CPD1 attenuates pulmonary arterial hypertension through dual modulation of cGMP and TRPM8-mediated pathways,” was published in Bioorganic Chemistry.
Enzyme blockers
PAH is marked by abnormally high pressure in the vessels that carry blood from the heart to the lungs. This puts strain on the right side of the heart, which is responsible for pumping blood to the lungs.
Several approved PAH treatments, including Adcirca (tadalafil) and Revatio (sildenafil), work by inhibiting the activity of the PDE5 enzyme. Blocking this enzyme leads to an increase in levels of the signaling molecule cyclic guanosine monophosphate (cGMP), which in turn causes blood vessels to relax and widen, decreasing blood pressure.
Both Adcirca and Revatio have been proven to help improve exercise ability in people with PAH. But they have a major drawback: Their active ingredients don’t dissolve very well in water, which can make it harder for them to be effectively absorbed by the body.
Seeking to address this issue, the team created a PDE5 inhibitor that would more easily dissolve in water.
Results from rat experiments showed that CPD1 decreased pressure in the lungs’ vessels and reduced signs of strain on the right side of the heart. These effects were achieved with a lower dose than what would typically be needed with Adcirca, the researchers noted.
The scientists also found that their PDE5 inhibitor might exert effects beyond the well-described cGMP-mediated pathway. For example, they found that, in addition to activating that pathway, CPD1 treatment led to an increase in the levels of a protein called transient receptor potential melastatin-8 (TRPM8) in blood vessel cells. This protein is known to help promote blood vessel relaxation, and previous studies have shown that TRPM8 levels are abnormally low in PAH.
“Our findings position CPD1 not merely as a more soluble PDE5 inhibitor but as a first-in-class agent that simultaneously modulates the cGMP pathway and the TRPM8 channel, offering a promising new therapeutic strategy … in PAH,” the researchers wrote.
