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Fetro. Rare Dis Orphan Drugs J 2023;2:7 https://dx.doi.org/10.20517/rdodj.2023.06 Page 3 of 16

was approved in Europe and the United States in 1998.

After its serendipitous repurposing for erectile dysfunctions, sildenafil was then repurposed (on purpose
[10]
this time) for a rare disease called pulmonary arterial hypertension . This indication was approved in
[11]
Europe and the United States in 2005 .

Of note, sildenafil acts on the same target: phosphodiesterase 5 (PDE5), to treat both erectile dysfunction
and pulmonary arterial hypertension. PDE5 is a key enzyme involved in the regulation of cyclic guanosine
monophosphate (cGMP)-specific signaling pathways in normal physiological processes, such as smooth
muscle contraction and relaxation.

Sildenafil was originally tested for angina pectoris, a chest pain associated with coronary heart disease. Since
PDE5 hydrolyzes cGMP in the cardiopulmonary vasculature, researchers aimed to establish a new anti-
anginal agent using PDE5 inhibitors to prolong cGMP activity and promote vasodilation of the coronary
arteries. However, early unconvincing results suggesting PDE5 was minimally present in cardiomyocytes led
to the abandonment of this research approach . PDE5 is the predominant PDE in the corpus cavernosum.
[12]
The catalytic site of PDE5 degrades cGMP, the key second messenger in the mediation of penile erection. In
men with erectile dysfunction, selective inhibition of PDE5 leads to an increase of cGMP in corpus
cavernosal tissue and improves erectile function.

Persistent pulmonary arterial hypertension (PAH) in newborns has been shown to be linked to PDE5
overexpression and overactivation. PAH is characterized by increased pulmonary vascular resistance due to
vasoconstriction of the small pulmonary arteries and arterioles. In blood vessels, cGMP relaxes vascular
smooth muscles leading to vasodilation and increased blood flow. By inhibiting PDE5 and raising the
intracellular cGMP, sildenafil is an effective pulmonary vasodilator.

Understanding the mechanisms of action (MOAs) of drugs is critical not only for drug development but
also for DR.

The identification of drug MOAs has been primarily based on pharmacological experiments.

Identification of MOAs through biological pathways involving a drug and its targets is a more recent
alternative approach to point to diseases not currently treated by a drug, to predict new uses of existing
drugs and to repurpose them. Such an approach can be of real interest also for drugs with unknown
underlying mechanisms.

In fact, biological pathway analysis based on drug targets (genes and proteins) may reveal new MOAs and
also new clinical functions of existing drugs . Alpelisib provides a good example of innovative DR in this
[13]
respect by illustrating how the analysis of a biological pathway can lead to the treatment of diseases other
than those initially investigated.

Alpelisib, an inhibitor of PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit
Alpha), was primarily developed for the treatment of PIK3CA-mutated cancers and then repurposed for the
treatment of PIK3CA-related overgrowth spectrum (PROS).