Repurposing of the PDE5 Inhibitor Sildenafil for the Treatment of Persistent Pulmonary Hypertension in Neonates

Erika    L.    Poitras; Stephen    L.    Gust; Paul    M.    Kerr; Frances       Plane
doi:10.2174/0929867327666200923151924
Abstract

Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca²⁺ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.
Keywords: Sildenafil, nitric oxide, pulmonary hypertension, phosphodiesterase inhibitor, cyclic GMP, neonate.
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DOI https://dx.doi.org/10.2174/0929867327666200923151924	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Repurposing of the PDE5 Inhibitor Sildenafil for the Treatment of Persistent Pulmonary Hypertension in Neonates

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