Can hydrolyze both cAMP and cGMP

PDE3A inhibitors are drugs which inhibits the action of the phosphodiesterase enzyme isoform 3A (PDE3A). They are used for the therapy of acute heart failure and cardiogenic shock. The cardiovascular bipyridines amrinone and milrinone are positive inotropic agents with vasodilator properties. PDE3A inhibitors, as their name suggests, blocks the breakdown of cAMP, increasing cytosolic calcium levels and leading to a positive inotropic effect: they increase the force of cardiac contraction. Amrinone, milrinone and enoximone are used clinically for short-term treatment of cardiac failure (el Allaf et al. 1984, Honerjäger 1989).

Milrinone (brand name Primacor) is a PDE3A inhibitor drug used in patients with heart failure (Hamada et al. 1999, DiBianco et al. 1989, Benotti et al. 1985). Studies in dogs indicate that by inhibiting PDE3A, milrinone and amrinone prevent cAMP degradation and thereby increase cAMP levels. This increases the activation of protein kinase A (PKA), an enzyme that phosphorylates components of the contractile machinery in muscle cells, including the heart (Alousi & Johnson 1986). Amrinone (INN, inamrinone), is a pyridine phosphodiesterase 3A (PDE3A) inhibitor drug that may improve the prognosis in patients with congestive heart failure (Hamada et al. 1999, Wilmshurst et al. 1984). It may also possess a vasodilatory effect (Ono et al. 1996, Wilmshurst et al. 1984). Enoximone is an imidazole PDE3A inhibitor (Dage et al. 1982) used in the treatment of congestive heart failure (Weber et al. 1986). Anagrelide is an oral imidazoquinazoline agent possessing anti-PDE3A activity and inhibits platelet aggregation in both humans and animals (Tefferi et al. 1997). Cilostazol is a quinolinone derivative acting as an antiplatelet agent with vasodilating properties (Schror 2002). It is used in the symptomatic treatment of intermittent claudication (pain in legs when walking but paid disappears on rest) in patients with peripheral ischaemia (Farkas et al. 2020). Ibudilast is an anti-inflammatory and neuroprotective oral agent used for the treatment of multiple sclerosis, asthma, and cerebrovascular disease (Yamazaki et al. 2011).

PDE activity may increase in a variety of tumours therfore PDE inhibitors may be potential targets for tumour cell growth inhibition and induction of apoptosis (Davari et al. 2014, Nazir et al. 2017, An et al. 2019).

Given that PDE inhibitors are used in the treatment of pathologies (eg thrombosis, inflammation, fibrosis) that can significantly overlap Covid-19 clinical symptoms, these drugs may be beneficial for the treatment of Covid-19 infection (Giorgi et al. 2020).

Cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes that regulate signal transduction by the second messenger molecules cAMP and cGMP (Maurice 2005). PDEs are important as drug targets:PDE3A inhibition promotes cardiac muscle contraction, a strategy used in heart failure.