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Review
. 2023 Sep 6;16(9):1266.
doi: 10.3390/ph16091266.

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Ahmed K ElHady  1 , Dalia S El-Gamil  2 , Mohammad Abdel-Halim  3 , Ashraf H Abadi  3
Affiliations
Review

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Ahmed K ElHady et al. Pharmaceuticals (Basel). .

Abstract

Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.

Keywords: NO/cGMP; erectile dysfunction; phosphodiesterase 5 inhibitors; pulmonary arterial hypertension; selectivity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of marketed PDE5 inhibitors.
Figure 2
Figure 2
Approved clinical uses of PDE5 inhibitors. Nitric oxide (NO) is produced by neurons and endothelial cells. Inside smooth muscle cells, NO activates soluble guanylyl cyclase (sGC), promoting the conversion of guanosine triphosphate (GTP) to the second messenger cyclic guanosine monophosphate (cGMP). Thereafter, cGMP activates protein kinase G (PKG), whose phosphorylation mediates activities of various membrane channels/pumps, leading to decreased intracellular calcium levels resulting in smooth muscle relaxation (SMR). Phosphodiesterase 5 (PDE5) regulates cGMP levels by degrading it into inactive 5′ guanosine monophosphate (5′ GMP). PDE5-Is can thus enhance the cGMP/PKG pathway, boosting the relaxation of various smooth muscles. In the penis corpus cavernosum, SMR favors erection due to increased penile arterial inflow, and thus PDE5-Is are approved for the treatment of erectile dysfunction. In the lungs, PDE5-Is lead to vasodilation of pulmonary vasculature, which, along with other mechanisms, such as suppressed DNA synthesis and proliferation and enhanced apoptosis of pulmonary artery cells, increased endothelial progenitor cell number, and enhanced release of vasodilating adenosine triphosphate (ATP) from erythrocytes culminate in effectiveness in the treatment of pulmonary arterial hypertension (PAH). In the lower urinary tract (LUT), PDE5-Is mediate prostate and bladder SMR, vasodilation and increased LUT oxygen perfusion. In addition, PDE5-Is could suppress prostatitis, bladder afferent nerve activity and prostate stroma cell proliferation, and thus indicated in the treatment of LUT symptoms secondary to benign prostatic hyperplasia (BPH).
Figure 3
Figure 3
Anti-cancer mechanisms of PDE5 inhibitors. Via activation of the cGMP/PKG signaling cascade, PDE5-Is can induce apoptosis in cancer cells via various pathways; activation of c-Jun NH2-terminal kinase (JNK) via phosphorylation of mitogen-activated protein kinase kinase kinase 1 (MEKK1), phosphorylation of β-catenin and inducing its proteosomal degradation which leads to decreased expression of Wnt/β-catenin regulated proteins, such as cyclin D1 and survivin in addition to blocking the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways. PDE5-Is could also increase intracellular levels of other chemotherapeutic agents via inhibition of the ATP-binding cassette (ABC) transporter-mediated drug efflux, averting multidrug resistance (MDR) in addition to increasing cellular drug uptake via enhancing endocytosis. Moreover, PDE5-Is synergize with other chemotherapeutic agents via boosting various apoptotic, autophagy, mitotic arrest and chaperone degradation pathways. PDE5-Is can also abrogate the function of myeloid-derived suppressor cells (MDSCs) via suppression of arginase-1 (Arg-1) and nitric oxide synthase–2 (NOS-2) production. This results in enhanced intratumoral T-cell infiltration and activation and restores both systemic and tumor-specific immunity. P = phosphorylation.
Figure 4
Figure 4
Emerging central nervous system (CNS)-related indications of PDE5 inhibitors. In Alzheimer’s disease (AD) and cognitive deficiency disease models, PDE5 inhibition increases presynaptic cGMP levels, which, through PKG activation, enhances the release of glutamate and activates N-methyl-D-aspartate receptors (NMDAR). On the other hand, postsynaptic PKG activates transcription factor cyclic adenosine monophosphate (cAMP) response element-binding element (CREB), promoting neurotransmission, synaptic plasticity and memory consolidation. PKG also activates the PI3K/AKT signaling pathway that mediates neuroprotection via the inhibition of apoptosis and also suppresses tau hyper-phosphorylation via inhibition of glycogen synthase kinase-3 beta (GSK3β). Elevated cGMP levels exhibit other cognitive enhancement mechanisms, such as vasodilation, which improves or maintains cerebrovascular endothelial function, preventing Aβ amyloid accumulation, rise in acetylcholine (ACh) and brain-derived neurotrophic factor (BDNF) levels in the cortex, striatum, and other areas of the brain, facilitation of neurogenesis, suppression of neuroinflammation and oxidative stress, all averting neuronal loss. In strokes, PDE5-Is could induce angiogenesis and neurogenesis and enhance cerebral blood flow to ischemic regions. PDE5-Is have anxiolytic effects in part due to enhanced oxytocin release. Moreover, PDE5-Is can promote efficient reconstitution of the myelin sheath and govern the Inflammatory processes involved in demyelination models of multiple sclerosis. PDE5-Is are also beneficial in noise-induced hearing loss via activating cGMP/protein kinase cGMP-dependent 1/poly (ADP-ribose) polymerase (cGMP/PRKG1/PARP) signaling in response to traumas in cochlea sensory cells. PDE5-Is exhibit pain-relieving effects in neuropathic pain models via enhanced release of gamma-aminobutyric acid (GABA). P = phosphorylation.
Figure 5
Figure 5
Cardioprotective effects of PDE5 inhibitors. PDE5-Is restore high cGMP levels in cardiomyocytes that govern diverse downstream cardioprotective mechanisms: (i) PKG-dependent opening of mitochondrial and sarcolemmal ATP-sensitive potassium channels, inhibition of Na+/H+-exchanger and release of endogenous cardioprotective molecules, such as adenosine, bradykinin from endothelial cells; resulting in reduced infarct size and hampered post-infarct left ventricular (LV) remodeling. All are beneficial for ischemic post-conditioning protection against myocardial infarction (MI) and ischemic reperfusion (I/R) injury, (ii) PKG-dependent suppression of adrenergic drive which reduces nerve growth factor leading to anti-arrhythmic effects, (iii) suppression of protein kinase C (PKC), calcineurin and RhoA/Rho-kinase pathways and (vi) suppression of oxidative stress and improving mitochondrial ultrastructure and function via increased sirtuin-3 (Sirt3) protein expression and decreased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) acetylation, all culminating in improved cardiac contractility and protection against heart failure (HF) and doxorubicin(dox)-induced cardiomyopathy.
Figure 6
Figure 6
Summary of approved and emerging/future uses of PDE5 inhibitors.
Figure 7
Figure 7
The discovery of sildenafil and vardenafil.
Figure 8
Figure 8
The discovery of tadalafil.
See this image and copyright information in PMC

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