The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

Paes, Dean; Schepers, Melissa; Rombaut, Ben; Hove, Daniël L.A. van den; Vanmierlo, Tim; Prickaerts, Jos

doi:10.1124/pharmrev.120.000273

Cited by 42 publications

(70 citation statements)

References 291 publications

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“…Alternatively, one could also postulate that a critical role of a particular PDE4 subtype on body temperature may have been obscured in the response of the respective PDE4 knockout mouse by compensatory changes in the expression or activity of the three other PDE4 isoforms. We consider this unlikely, however, given the large body of data suggesting that PDEs are not functionally interchangeable [ 3 , 88 , 89 ] and because such compensatory changes in PDE4 expression were not observed in various primary cells or tissues of PDE4-KO mice reported previously [ 19 , 20 , 22 , 23 , 52 , 61 , 90 , 91 , 92 ].…”

Section: Discussionmentioning

confidence: 97%

“…Type 4 cyclic nucleotide phosphodiesterases (PDE4s) comprise a group of four isoenzymes, PDE4A to D, that hydrolyze and inactivate the second messenger cAMP. PDE4s are widely expressed throughout mammalian cells and tissues [ 1 , 2 , 3 , 4 , 5 ], and diverse therapeutic benefits result from their non/PAN-selective inhibition. Preclinical studies of PAN-PDE4 inhibitors have established their potent anti-inflammatory, memory- and cognition-enhancing, anti-depressant and anti-psychotic, metabolic, and cardiovascular properties [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…PDE4s are widely expressed throughout mammalian cells and tissues [ 1 , 2 , 3 , 4 , 5 ], and diverse therapeutic benefits result from their non/PAN-selective inhibition. Preclinical studies of PAN-PDE4 inhibitors have established their potent anti-inflammatory, memory- and cognition-enhancing, anti-depressant and anti-psychotic, metabolic, and cardiovascular properties [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, the clinical application and commercial success of PDE4 inhibitors have been muted due to adverse effects, particularly nausea, diarrhea, and emesis.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

Boyd

Aragon

Rich

et al. 2021

Biology

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Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

Boyd

Aragon

Rich

et al. 2021

Biology

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“…Only in 1996, it become evident that a better side-effect profile could be obtained with agents preferentially targeting the catalytic site over HARBS [ 65 ]. Then, this type of selectivity was not pursued any longer, and another type of selectivity versus the gene products A-D was proposed after these subtypes were characterized, their tissue distribution demonstrated and their different functional role suggested [ 66 ]. In the early 2000s, the PDE4D isoform was indicated as being responsible for PDE4 inhibitor-induced emesis [ 67 ], although recent studies suggest that it may not be the only factor involved in this side effect [ 68 ]; on the other hand, it has been demonstrated that PDE4B selective inhibitors produce potent anti-inflammatory and reduced emetic effects [ 69 ].…”

Section: From In Vitro and Preclinical Profile Of The First Pde 4 Inh...mentioning

confidence: 99%

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022

et al. 2022

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Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

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“…The approval and clinical use of PDE4 inhibitors for the treatment of major human inflammatory disorders demonstrates the tremendous progress over the last 7 years, with indications expanding at an almost yearly pace. PDE4-selective inhibitors have now been approved for the oral treatment of chronic obstructive pulmonary disease [ 6 ], psoriatic arthritis and plaque psoriasis [ 7 ], and as a topical treatment for atopic dermatitis [ 8 ]; they are also being considered as therapeutics for diseases of the CNS [ 9 , 10 ]. Hence, PDE inhibitors are proving to be of great clinical benefit in inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8)

Basole

Nguyen

Lamothe

et al. 2022

Cells

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After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) activated CD4+ effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity. In this study, we explored the in vivo treatment of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) induced in mice immunized with MOG using the PDE8-selective inhibitor PF-04957325. For treatment in vivo, mice with EAE were either subcutaneously (s.c.) injected three times daily (10 mg/kg/dose), or were implanted subcutaneously with Alzet mini-osmotic pumps to deliver the PDE8 inhibitor (15.5 mg/kg/day). The mice were scored daily for clinical signs of paresis and paralysis which were characteristic of EAE. We observed the suppression of the clinical signs of EAE and a reduction of inflammatory lesion formation in the CNS by histopathological analysis through the determination of the numbers of mononuclear cells isolated from the spinal cord of mice with EAE. The PDE8 inhibitor treatment reduces the accumulation of both encephalitogenic Th1 and Th17 T cells in the CNS. Our study demonstrates the efficacy of targeting PDE8 as a treatment of autoimmune inflammation in vivo by reducing the inflammatory lesion load.

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The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

Cited by 42 publications

References 291 publications

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022

Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8)

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