Phosphodiesterases (PDEs), enzymes that degrade 3′,5′-cyclic nucleotides, are being pursued as therapeutic targets for several diseases, including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Clinical development programmes have focused exclusively on catalytic inhibition, which continues to be a strong focus of ongoing drug discovery efforts. However, emerging evidence supports novel strategies to therapeutically target PDE function, including enhancing catalytic activity, normalizing altered compartmentalization and modulating post-translational modifications, as well as the potential use of PDEs as disease biomarkers. Importantly, a more refined appreciation of the intramolecular mechanisms regulating PDE function and trafficking is emerging, making these pioneering drug discovery efforts tractable.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Maurice, D. H. et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat. Rev. Drug Discov. 13, 290–314 (2014).
Schneider, E. H. & Seifert, R. Inactivation of non-canonical cyclic nucleotides: hydrolysis and transport. Handb. Exp. Pharmacol. 238, 169–205 (2017). This work is a helpful review of the role PDEs play in regulating non-canonical cyclic nucleotides.
Herbst, S. et al. Transmembrane redox control and proteolysis of PdeC, a novel type of c-di-GMP phosphodiesterase. EMBO J. 37, e97825 (2018).
Seifert, R. cCMP and cUMP across the tree of life: from cCMP and cUMP generators to cCMP- and cUMP-regulated cell functions. Handb. Exp. Pharmacol. 238, 3–23 (2017).
Patel, N. S. et al. Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span. Neurobiol. Aging 65, 217–234 (2018). This study is a first report showing that the subcellular compartmentalization of a PDE family differs depending on the specific isoform, age and tissue investigated.
Huston, E., Gall, I., Houslay, T. M. & Houslay, M. D. Helix-1 of the cAMP-specific phosphodiesterase PDE4A1 regulates its phospholipase-D-dependent redistribution in response to release of Ca2+. J. Cell Sci. 119, 3799–3810 (2006). This study provides the first evidence that PDEs can be relocated by Ca 2+ , providing a potential mechanism by which cAMP, phospholipase D and Ca 2+ -signalling pathways interact.
Nagel, D. J. et al. Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circ. Res. 98, 777–784 (2006).
Houslay, M. D. & Baillie, G. S. Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of beta2-adrenoceptor signalling to activation of ERK. Biochem. Soc. Trans. 33, 1333–1336 (2005).
Perera, R. K. et al. Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of beta-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ. Res. 116, 1304–1311 (2015). This study is an important work showing that the subcellular compartmentalization of a PDE may change with disease.
Penmatsa, H. et al. Compartmentalized cyclic adenosine 3΄,5΄-monophosphate at the plasma membrane clusters PDE3A and cystic fibrosis transmembrane conductance regulator into microdomains. Mol. Biol. Cell 21, 1097–1110 (2010).
Ahmad, F. et al. Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta3-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes. Biochem. J. 424, 399–410 (2009). The results of this study suggest elevations in cAMP can trigger a subcellular redistribution of PDEs.
Al-Tawashi, A. & Gehring, C. Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. Cell Commun. Signal. 11, 47 (2013).
Bonkale, W. L., Winblad, B., Ravid, R. & Cowburn, R. F. Reduced nitric oxide responsive soluble guanylyl cyclase activity in the superior temporal cortex of patients with Alzheimer’s disease. Neurosci. Lett. 187, 5–8 (1995). This work is an example of a human study showing that cyclic nucleotide signalling deficits associated with disease can be specific to a particular subcellular compartment.
Baltrons, M. A., Pifarre, P., Ferrer, I., Carot, J. M. & Garcia, A. Reduced expression of NO-sensitive guanylyl cyclase in reactive astrocytes of Alzheimer disease, Creutzfeldt-Jakob disease, and multiple sclerosis brains. Neurobiol. Dis. 17, 462–472 (2004).
Baltrons, M. A., Pedraza, C. E., Heneka, M. T. & Garcia, A. Beta-amyloid peptides decrease soluble guanylyl cyclase expression in astroglial cells. Neurobiol. Dis. 10, 139–149 (2002).
Yarla, N. S. et al. Targeting the paracrine hormone-dependent guanylate cyclase/cGMP/phosphodiesterases signaling pathway for colorectal cancer prevention. Semin. Cancer Biol. 56, 168–174 (2018).
Li, N. et al. Suppression of beta-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 6, 27403–27415 (2015).
Lee, D. I. et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519, 472–476 (2015). This study clarifies that, in the heart, PDE9 regulates pools of cGMP downstream of particulate guanylyl cyclases whereas PDE5 regulates pools of cGMP downstream of soluble guanylyl cyclases.
Hartell, N. A., Furuya, S., Jacoby, S. & Okada, D. Intercellular action of nitric oxide increases cGMP in cerebellar Purkinje cells. Neuroreport 12, 25–28 (2001).
Rahman, S. et al. Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J. Neurochem. 68, 297–304 (1997). This work is another example of a human study showing cyclic nucleotide signalling deficits associated with disease can be specific to a particular subcellular compartment.
Mori, S. et al. Effects of lithium on cAMP-dependent protein kinase in rat brain. Neuropsychopharmacology 19, 233–240 (1998).
Francis, S. H. & Corbin, J. D. Phosphodiesterase-5 inhibition: the molecular biology of erectile function and dysfunction. Urol. Clin. North Am. 32, 419–429 (2005).
Schwartz, B. G. & Kloner, R. A. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation 122, 88–95 (2010).
Zoccarato, A. et al. Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2. Circ. Res. 117, 707–719 (2015).
Kaname, T. et al. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell. Signal. 26, 2446–2459 (2014).
Motte, E., Le Stunff, C., Briet, C., Dumaz, N. & Silve, C. Modulation of signaling through GPCR–cAMP–PKA pathways by PDE4 depends on stimulus intensity: possible implications for the pathogenesis of acrodysostosis without hormone resistance. Mol. Cell. Endocrinol. 442, 1–11 (2017).
Boscutti, G., Rabiner, E. A. & Plisson, C. PET radioligands for imaging of the PDE10A in human: current status. Neurosci. Lett. 691, 11–17 (2019).
Russell, D. S. et al. Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging. Neurology 86, 748–754 (2016).
Heckman, P. R. A., Blokland, A., Bollen, E. P. P. & Prickaerts, J. Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: clinical overview and translational considerations. Neurosci. Biobehav. Rev. 87, 233–254 (2018).
[No authors listed.] Vinpocetine. Monograph. Altern. Med. Rev. 7, 240–243 (2002).
Asal, N. J. & Wojciak, K. A. Effect of cilostazol in treating diabetes-associated microvascular complications. Endocrine 56, 240–244 (2017).
Chapman, T. M. & Goa, K. L. Cilostazol: a review of its use in intermittent claudication. Am. J. Cardiovasc. Drugs 3, 117–138 (2003).
Chong, L. Y. Z., Satya, K., Kim, B. & Berkowitz, R. Milrinone dosing and a culture of caution in clinical practice. Cardiol. Rev. 26, 35–42 (2018).
Celli, B. R. Pharmacological therapy of COPD: reasons for optimism. Chest 154, 1404–1415 (2018).
Cada, D. J., Ingram, K. & Baker, D. E. Apremilast. Hosp. Pharm. 49, 752–762 (2014).
Papp, K. et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (efficacy and safety trial evaluating the effects of apremilast in psoriasis [ESTEEM] 1). J. Am. Acad. Dermatol. 73, 37–49 (2015).
Edwards, C. J. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann. Rheum. Dis. 75, 1065–1073 (2016).
Terburg, D. et al. Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus. Neuropsychopharmacology 38, 2708–2716 (2013).
Chiu, S. et al. Proof-of-concept randomized controlled study of cognition effects of the proprietary extract Sceletium tortuosum (Zembrin) targeting phosphodiesterase-4 in cognitively healthy subjects: implications for Alzheimer’s dementia. Evid. Based Complement. Alternat. Med. 2014, 682014 (2014).
Campbell, H. E. Clinical monograph for drug formulary review: erectile dysfunction agents. J. Manag. Care Pharm. 11, 151–171 (2005).
Cho, M. C. & Paick, J. S. Udenafil for the treatment of erectile dysfunction. Ther. Clin. Risk Manag. 10, 341–354 (2014).
Kang, S. G. & Kim, J. J. Udenafil: efficacy and tolerability in the management of erectile dysfunction. Ther. Adv. Urol. 5, 101–110 (2013).
Shim, Y. S. et al. Effects of daily low-dose treatment with phosphodiesterase type 5 inhibitor on cognition, depression, somatization and erectile function in patients with erectile dysfunction: a double-blind, placebo-controlled study. Int. J. Impot. Res. 26, 76–80 (2014).
Shim, Y. S. et al. Effects of repeated dosing with udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study. Int. J. Impot. Res. 23, 109–114 (2011).
Helal, C. J. et al. Identification of a potent, highly selective, and brain penetrant phosphodiesterase 2A Inhibitor clinical candidate. J. Med. Chem. 61, 1001–1018 (2018).
[No authors listed.] Exisulind: aptosyn, FGN 1, prevatac, sulindac sulfone. Drugs R. D. 5, 220–226 (2004).
Griffiths, G. J. Exisulind cell pathways. Curr. Opin. Investig. Drugs 1, 386–391 (2000).
Rosales, R. L., Santos, M. M. & Mercado-Asis, L. B. Cilostazol: a pilot study on safety and clinical efficacy in neuropathies of diabetes mellitus type 2 (ASCEND). Angiology 62, 625–635 (2011).
Giembycz, M. A. An update and appraisal of the cilomilast phase III clinical development programme for chronic obstructive pulmonary disease. Br. J. Clin. Pharmacol. 62, 138–152 (2006).
Ratziu, V. et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 12, 1724–1730 (2014).
Schultheiss, D. et al. Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials. World J. Urol. 19, 46–50 (2001).
Grass, H. et al. Sildenafil (Viagra): is there an influence on psychological performance? Int. Urol. Nephrol. 32, 409–412 (2001).
Reneerkens, O. A. et al. The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study. J. Psychopharmacol. 27, 600–608 (2013).
Reneerkens, O. A. et al. The PDE5 inhibitor vardenafil does not affect auditory sensory gating in rats and humans. Psychopharmacology 225, 303–312 (2013).
Goff, D. C. et al. A placebo-controlled study of sildenafil effects on cognition in schizophrenia. Psychopharmacology 202, 411–417 (2009).
Akhondzadeh, S. et al. Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. Psychopharmacology 213, 809–815 (2011).
Nelson, M. D. et al. PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82, 2085–2091 (2014).
Martin, E. A. et al. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy. Sci. Transl Med. 4, 162ra155 (2012).
Schwam, E. M. et al. A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s disease. Curr. Alzheimer Res. 11, 413–421 (2014). Despite proving target engagement by measuring a change in cerebrospinal fluid cGMP levels, this clinical trial failed to detect any significant behavioural effect of a PDE9 inhibitor in patients with AD.
Boehringer Ingelheim International GmbH. Boehringer Ingelheim refocuses PDE9 inhibition brain research on schizophrenia following results from phase II Alzheimer’s trials. Boehringer Ingelheim https://www.boehringer-ingelheim.com/PDE9-Inhibition-in-AD (2018).
Brown, D. et al. Evaluation of the efficacy, safety, and tolerability of BI 409306, a novel phosphodiesterase 9 inhibitor, in cognitive impairment in schizophrenia: a randomized, double-blind, placebo-controlled, phase II trial. Schizophr. Bull. 45, 350–359 (2018).
Moschetti, V. et al. The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: overview of three phase I randomised trials in healthy volunteers. Eur. Neuropsychopharmacol. 28, 643–655 (2018).
Brown, D., Daniels, K., Pichereau, S., & Sand, M. A. Phase IC study evaluating the safety, tolerability, pharmacokinetics, and cognitive outcomes of BI 409306 in patients with mild-to-moderate schizophrenia. Neurol. Ther. 7, 129–139 (2018).
Wunderlich, G. et al. Study design and characteristics of two phase II proof-of-concept clinical trials of the pde9 inhibitor BI 409306 in early Alzheimer’s disease. Alzheimers Dement. 12, P820–P821 (2016).
Grauer, S. M. et al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J. Pharmacol. Exp. Ther. 331, 574–590 (2009).
Schmidt, C. J. et al. Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J. Pharmacol. Exp. Ther. 325, 681–690 (2008).
DeMartinis, N. et al. Results of a phase 2A proof-of-concept trial with a PDE10A inhibitor in the treatment of acute exacerbation of schizophrenia. Schizophr. Res. 136, S262 (2012).
Russell, D. S. et al. The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease. JAMA Neurol. 71, 1520–1528 (2014).
Beaumont, V. et al. Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models. Neuron 92, 1220–1237 (2016).
Kelly, M. P. in Encyclopedia of Signaling Molecules (ed. Choi, S.) 3804–3826 (Springer International Publishing, 2018).
Kelly, M. P. et al. Select 3΄,5΄-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain. Cell. Signal. 26, 383–397 (2014). This study directly compares expression patterns of all brain-expressed PDEs using both in situ hybridization and PCR in mouse and rat brains.
Raheem, I. T. et al. Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. Bioorg. Med. Chem. Lett. 26, 126–132 (2016).
Burgin, A. B. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat. Biotechnol. 28, 63–70 (2010). This study presents a rare example of a PDE inhibitor that does not simply compete for the catalytic site.
Hagen, T. J. et al. Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg. Med. Chem. Lett. 24, 4031–4034 (2014). This study is an important example of how knowledge of biology can drive more sophisticated medicinal chemistry efforts that end up achieving more selective pharmacological targeting of a given PDE.
Pushpakom, S. et al. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 18, 41–58 (2018).
Ledeboer, A., Hutchinson, M. R., Watkins, L. R. & Johnson, K. W. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin. Investig. Drugs 16, 935–950 (2007).
Schwenkgrub, J., Zaremba, M., Mirowska-Guzel, D. & Kurkowska-Jastrzebska, I. Ibudilast: a nonselective phosphodiesterase inhibitor in brain disorders. Postepy Hig. Med. Dosw. 71, 137–148 (2017).
DeYoung, D. Z. et al. Safety of intravenous methamphetamine administration during ibudilast treatment. J. Clin. Psychopharmacol. 36, 347–354 (2016).
Worley, M. J., Swanson, A. N., Heinzerling, K. G., Roche, D. J. & Shoptaw, S. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend. 162, 245–250 (2016).
Cooper, Z. D. et al. Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers. Drug Alcohol Depend. 178, 340–347 (2017).
Ray, L. A. et al. Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: a randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacology 42, 1776–1788 (2017).
Snyder, G. L. et al. Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats. Psychopharmacology 233, 3113–3124 (2016).
Li, P. et al. Discovery of potent and selective inhibitors of phosphodiesterase 1 for the treatment of cognitive impairment associated with neurodegenerative and neuropsychiatric diseases. J. Med. Chem. 59, 1149–1164 (2016).
Pekcec, A. et al. Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase-1 improves cognitive performance. Br. J. Pharmacol. 175, 3021–3033 (2018).
Dyck, B. et al. Discovery of selective phosphodiesterase 1 inhibitors with memory enhancing properties. J. Med. Chem. 60, 3472–3483 (2017).
Hashimoto, T. et al. Acute enhancement of cardiac function by phosphodiesterase type 1 inhibition — translational study in the dog and rabbit. Circulation 138, 1974–1987 (2018).
Zhang, C., Lueptow, L. M., Zhang, H. T., O’Donnell, J. M. & Xu, Y. The role of phosphodiesterase-2 in psychiatric and neurodegenerative disorders. Adv. Neurobiol. 17, 307–347 (2017).
Mikami, S. et al. Discovery of a novel series of pyrazolo[1,5-a]pyrimidine-based phosphodiesterase 2A inhibitors structurally different from N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the treatment of cognitive disorders. Chem. Pharm. Bull. 65, 1058–1077 (2017).
Mikami, S. et al. Discovery of clinical candidate N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): a highly potent, selective, and brain-penetrating phosphodiesterase 2A inhibitor for the treatment of cognitive disorders. J. Med. Chem. 60, 7677–7702 (2017).
Mikami, S. et al. Discovery of an orally bioavailable, brain-penetrating, in vivo active phosphodiesterase 2A inhibitor lead series for the treatment of cognitive disorders. J. Med. Chem. 60, 7658–7676 (2017).
Weber, S. et al. PDE2 at the crossway between cAMP and cGMP signalling in the heart. Cell. Signal. 38, 76–84 (2017).
Zhang, C. et al. The roles of phosphodiesterase 2 in the central nervous and peripheral systems. Curr. Pharm. Des. 21, 274–290 (2015).
Bundhun, P. K., Qin, T. & Chen, M. H. Comparing the effectiveness and safety between triple antiplatelet therapy and dual antiplatelet therapy in type 2 diabetes mellitus patients after coronary stents implantation: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc. Disord. 15, 118 (2015).
Neel, J. D., Kruse, R. L., Dombrovskiy, V. Y. & Vogel, T. R. Cilostazol and freedom from amputation after lower extremity revascularization. J. Vasc. Surg. 61, 960–964 (2015).
Lim, H. W. et al. Effect of a 4-week treatment with cilostazol in patients with chronic tinnitus: a randomized, prospective, placebo-controlled, double-blind, pilot study. J. Int. Adv. Otol. 12, 170–176 (2016).
Lakics, V., Karran, E. H. & Boess, F. G. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59, 367–374 (2010). This work presents a head-to-head comparison of PDE expression patterns in various human tissues.
Mochizuki, Y., Oishi, M. & Mizutani, T. Effects of cilostazol on cerebral blood flow, P300, and serum lipid levels in the chronic stage of cerebral infarction. J. Stroke Cerebrovasc. Dis. 10, 63–69 (2001).
Jung, K. I., Kim, J. H., Park, H. Y. & Park, C. K. Neuroprotective effects of cilostazol on retinal ganglion cell damage in diabetic rats. J. Pharmacol. Exp. Ther. 345, 457–463 (2013).
Masciarelli, S. et al. Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. J. Clin. Invest. 114, 196–205 (2004).
Taiyeb, A. M. et al. Cilostazol blocks pregnancy in naturally cycling swine: an animal model. Life Sci. 142, 92–96 (2015).
Taiyeb, A. M., Muhsen-Alanssari, S. A., Dees, W. L., Ridha-Albarzanchi, M. T. & Kraemer, D. C. Improvement in in vitro fertilization outcome following in vivo synchronization of oocyte maturation in mice. Exp. Biol. Med. 240, 519–526 (2015).
Duan, L. M., Yu, H. Y., Li, Y. L. & Jia, C. J. Design and discovery of 2-(4-(1H-tetrazol-5-yl)-1H-pyrazol-1-yl)-4-(4-phenyl)thiazole derivatives as cardiotonic agents via inhibition of PDE3. Bioorg. Med. Chem. 23, 6111–6117 (2015).
Kim, K. Y., Lee, H., Yoo, S. E., Kim, S. H. & Kang, N. S. Discovery of new inhibitor for PDE3 by virtual screening. Bioorg. Med. Chem. Lett. 21, 1617–1620 (2011).
Nikpour, M. et al. Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors. Bioorg. Med. Chem. 18, 855–862 (2010).
Huff, S. B. & Gottwald, L. D. Repigmentation of tenacious vitiligo on apremilast. Case Rep. Dermatol. Med. 2017, 2386234 (2017).
AbuHilal, M., Walsh, S. & Shear, N. Treatment of recalcitrant erosive oral lichen planus and desquamative gingivitis with oral apremilast. J. Dermatol. Case Rep. 10, 56–57 (2016).
Hafner, J. et al. Apremilast is effective in lichen planus mucosae-associated stenotic esophagitis. Case Rep. Dermatol. 8, 224–226 (2016).
Bettencourt, M. Oral lichen planus treated with apremilast. J. Drugs Dermatol. 15, 1026–1028 (2016).
Jensterle, M., Kocjan, T. & Janez, A. Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 99, E1476–E1481 (2014).
Jensterle, M., Salamun, V., Kocjan, T., Vrtacnik Bokal, E. & Janez, A. Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study. J. Ovarian Res. 8, 32 (2015).
Plock, N., Vollert, S., Mayer, M., Hanauer, G. & Lahu, G. Pharmacokinetic/pharmacodynamic modeling of the PDE4 inhibitor TAK-648 in type 2 diabetes: early translational approaches for human dose prediction. Clin. Transl Sci. 10, 185–193 (2017).
Van Duinen, M. A. et al. Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. Neuropharmacology 131, 31–38 (2018). This work is one of the first studies to demonstrate a pro-cognitive effect in humans of a commercially available PDE4 inhibitor.
Gilleen, J. et al. An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology https://doi.org/10.1007/s00213-018-5134-y (2018).
Blokland, A. et al. Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study. Neurobiol. Aging 77, 37–43 (2019).
Kanes, S. J. et al. Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 144, 239–246 (2007).
Kelly, M. P. et al. Constitutive activation of Gαs within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32, 577–588 (2007). This work is an important study showing that chronic signalling through Gα s will lead to PKA-dependent compensatory increases in PDE activity in some brain regions but not others.
Kelly, M. P. et al. Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Gαs, a G-protein subunit genetically linked to schizophrenia. Mol. Psychiatry 14, 398–415 (2009).
Rodefer, J. S., Saland, S. K. & Eckrich, S. J. Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology 62, 1182–1190 (2012).
Helicon Therapeutics, Inc. Helicon study of HT-0712 on primate memory formation reveals significant enhancement. Dart Neuroscience http://dartneuroscience.com/press_releases/july_22_2008.pdf (2008).
MacDonald, E. et al. A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia. Neurorehabil. Neural Repair 21, 486–496 (2007).
Peters, M. et al. The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice. Neuropsychopharmacology 39, 2938–2948 (2014).
Tetra Discovery Partners. Tetra Discovery Partners announces positive results from phase 1 studies of cognition drug candidate, BPN14770. Tetra Discovery http://tetradiscovery.com/wp-content/uploads/2016/11/FINAL-Tetra-Phase-1-121616-FINAL.pdf (2016).
Gurney, M. E., Cogram, P., Deacon, R. M., Rex, C. & Tranfaglia, M. Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4D (PDE4D). Sci. Rep. 7, 14653 (2017).
Zhang, C. et al. Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice. Neuropsychopharmacology 43, 2299–2309 (2018).
Rutter, A. R. et al. GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J. Pharmacol. Exp. Ther. 350, 153–163 (2014).
Munshi, A. & Das, S. Genetic understanding of stroke treatment: potential role for phosphodiesterase inhibitors. Adv. Neurobiol. 17, 445–461 (2017).
Chen, J. et al. The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia–reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion. Brain Res. Bull. 137, 98–106 (2018).
Soares, L. M. et al. Rolipram improves cognition, reduces anxiety- and despair-like behaviors and impacts hippocampal neuroplasticity after transient global cerebral ischemia. Neuroscience 326, 69–83 (2016).
Li, L. X. et al. Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. Metab. Brain Dis. 26, 37–47 (2011).
Titus, D. J. et al. A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury. Neurobiol. Learn. Mem. 148, 38–49 (2018).
Knott, E. P., Assi, M., Rao, S. N., Ghosh, M. & Pearse, D. D. Phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair. Int. J. Mol. Sci. 18, E696 (2017).
Olsen, C. M. & Liu, Q. S. Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities. Front. Biol. 11, 376–386 (2016).
Logrip, M. L. Phosphodiesterase regulation of alcohol drinking in rodents. Alcohol 49, 795–802 (2015).
Avila, D. V. et al. Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. J. Pathol. 240, 96–107 (2016).
Avila, D. V. et al. Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation. Neuropharmacology 125, 376–385 (2017).
Favilla, C., Abel, T. & Kelly, M. P. Chronic Gαs signaling in the striatum increases anxiety-related behaviors independent of developmental effects. J. Neurosci. 28, 13952–13956 (2008).
Kelly, M. P. et al. Constitutive activation of the G-protein subunit Gαs within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression. Learn. Mem. 15, 75–83 (2008).
Cooney, J. D. & Aguiar, R. C. Phosphodiesterase 4 inhibitors have wide-ranging activity in B cell malignancies. Blood 128, 2886–2890 (2016).
Wang, W. et al. Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition. Oncotarget 7, 87232–87245 (2016).
Nishi, K. et al. Apremilast induces apoptosis of human colorectal cancer cells with mutant KRAS. Anticancer Res. 37, 3833–3839 (2017).
Mishra, R. R. et al. Reactivation of cAMP pathway by PDE4D inhibition represents a novel druggable axis for overcoming tamoxifen resistance in ER-positive breast cancer. Clin. Cancer Res. 24, 1987–2001 (2018).
Wortsman, X., Del Barrio-Diaz, P., Meza-Romero, R., Poehls-Risco, C. & Vera-Kellet, C. Nifedipine cream versus sildenafil cream for patients with secondary Raynaud phenomenon: a randomized, double-blind, controlled pilot study. J. Am. Acad. Dermatol. 78, 189–190 (2018).
Maged, M., Wageh, A., Shams, M. & Elmetwally, A. Use of sildenafil citrate in cases of intrauterine growth restriction (IUGR); a prospective trial. Taiwan J. Obstet. Gynecol. 57, 483–486 (2018).
Pels, A. et al. STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials. BMC Pregnancy Childbirth 17, 440 (2017).
El-Sayed, M. A., Saleh, S. A., Maher, M. A. & Khidre, A. M. Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate. J. Matern. Fetal Neonatal Med. 31, 1045–1050 (2018).
Paauw, N. D. et al. Sildenafil during pregnancy: a preclinical meta-analysis on fetal growth and maternal blood pressure. Hypertension 70, 998–1006 (2017).
Aversa, A. et al. Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization. Endocrine 56, 639–648 (2017).
Giannetta, E. et al. Chronic inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 125, 2323–2333 (2012).
Di Luigi, L. et al. Phosphodiesterase type 5 inhibitor sildenafil decreases the proinflammatory chemokine CXCL10 in human cardiomyocytes and in subjects with diabetic cardiomyopathy. Inflammation 39, 1238–1252 (2016).
Fiore, D. et al. PDE5 inhibition ameliorates visceral adiposity targeting the miR-22/SIRT1 pathway: evidence from the CECSID trial. J. Clin. Endocrinol. Metab. 101, 1525–1534 (2016).
Mandosi, E. et al. Endothelial dysfunction markers as a therapeutic target for sildenafil treatment and effects on metabolic control in type 2 diabetes. Expert Opin. Ther. Targets 19, 1617–1622 (2015).
Santi, D. et al. Could chronic vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus? PLOS ONE 13, e0199299 (2018).
Montes Cardona, C. E. & Garcia-Perdomo, H. A. Efficacy of phosphodiesterase type 5 inhibitors for the treatment of distal ureteral calculi: a systematic review and meta-analysis. Investig. Clin. Urol. 58, 82–89 (2017).
Booth, L. et al. Neratinib augments the lethality of [regorafenib + sildenafil]. J. Cell. Physiol. 234, 4874–4887 (2018).
Islam, B. N. et al. Sildenafil suppresses inflammation-driven colorectal cancer in mice. Cancer Prev. Res. 10, 377–388 (2017).
Califano, J. A. et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 30–38 (2015).
Weed, D. T. et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 39–48 (2015).
Charych, E. I., Jiang, L. X., Lo, F., Sullivan, K. & Brandon, N. J. Interplay of palmitoylation and phosphorylation in the trafficking and localization of phosphodiesterase 10A: implications for the treatment of schizophrenia. J. Neurosci. 30, 9027–9037 (2010). This study presents a key finding showing that two PTMs can compete to regulate the subcellular compartmentalization of a PDE.
Lee, K. et al. β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7, 5353–5365 (2016).
Li, N. et al. Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and beta-catenin-dependent TCF transcriptional activity. Oncogene 34, 1499–1509 (2015).
Barone, I., Giordano, C., Bonofiglio, D., Ando, S. & Catalano, S. Phosphodiesterase type 5 and cancers: progress and challenges. Oncotarget 8, 99179–99202 (2017).
Aoun, F. et al. Association between phosphodiesterase type 5 inhibitors and prostate cancer: a systematic review. Prog. Urol. 28, 560–566 (2018).
Arozarena, I. et al. Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell 19, 45–57 (2011).
Feng, S. et al. Are phosphodiesterase type 5 inhibitors associated with increased risk of melanoma? A systematic review and meta-analysis. Medicine 97, e9601 (2018). This study presents an important reminder that attention must be paid not only to acute side-effect profiles, but also long-term risks of PDE-inhibitor treatment.
Almeida, C. B. et al. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 120, 2879–2888 (2012).
Goldsmith, P. et al. A randomized multiple dose pharmacokinetic study of a novel PDE10A inhibitor TAK-063 in subjects with stable schizophrenia and Japanese subjects and modeling of exposure relationships to adverse events. Drugs R. D. 17, 631–643 (2017).
Macek, T. A. et al. A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia. Schizophr. Res. 204, 289–294 (2019).
Suzuki, K., Harada, A., Suzuki, H., Miyamoto, M. & Kimura, H. TAK-063, a PDE10A inhibitor with balanced activation of direct and indirect pathways, provides potent antipsychotic-like effects in multiple paradigms. Neuropsychopharmacology 41, 2252–2262 (2016).
Wilson, J. M. et al. Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum. Neuropharmacology 99, 379–386 (2015).
Padovan-Neto, F. E. & West, A. R. Regulation of striatal neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition: implications for the treatment of Parkinson’s disease. Adv. Neurobiol. 17, 257–283 (2017).
Jankowska, A., Swierczek, A., Chlon-Rzepa, G., Pawlowski, M. & Wyska, E. PDE7-selective and dual inhibitors: advances in chemical and biological research. Curr. Med. Chem. 24, 673–700 (2017).
Redondo, M. et al. Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds. J. Med. Chem. 55, 3274–3284 (2012).
Morales-Garcia, J. A. et al. Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice. Neurobiol. Aging 36, 1160–1173 (2015).
Morales-Garcia, J. A. et al. Phosphodiesterase7 inhibition activates adult neurogenesis in hippocampus and subventricular zone in vitro and in vivo. Stem Cells 35, 458–472 (2017).
Tsai, L. C. et al. Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay. Genes Brain Behav. 11, 837–847 (2012).
Pilarzyk, K. et al. Loss of function of phosphodiesterase 11A4 shows that recent and remote long term memories can be uncoupled. Curr. Biol. https://doi.org/10.1016/j.cub.2019.06.018 (2019).
Pathak, G. et al. PDE11A negatively regulates lithium responsivity. Mol. Psychiatry 22, 1714–1724 (2017). This study not only identifies PDE homodimerization as a molecular mechanism regulating PDE protein stability and subcellular compartmentalization but also provides proof of principle for how homodimerization could be therapeutically targeted using a biologic.
Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015).
Dong, H., Zitt, C., Auriga, C., Hatzelmann, A. & Epstein, P. M. Inhibition of PDE3, PDE4 and PDE7 potentiates glucocorticoid-induced apoptosis and overcomes glucocorticoid resistance in CEM T leukemic cells. Biochem. Pharmacol. 79, 321–329 (2010).
de Medeiros, A. S. et al. Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays. Cell. Signal. 40, 73–80 (2017). This study reports a novel yeast-based assay for screening PDE modulators, which not only reads out changes in PDE activity but also proves compounds are cell permeable, are chemically stable and do not exhibit widespread protein binding.
Tsai, L. C., Shimizu-Albergine, M. & Beavo, J. A. The high-affinity cAMP-specific phosphodiesterase 8B controls steroidogenesis in the mouse adrenal gland. Mol. Pharmacol. 79, 639–648 (2011).
Shimizu-Albergine, M., Tsai, L. C., Patrucco, E. & Beavo, J. A. cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis. Mol. Pharmacol. 81, 556–566 (2012).
Jang, I. S. et al. Lysophosphatidic acid-induced changes in cAMP profiles in young and senescent human fibroblasts as a clue to the ageing process. Mech. Ageing Dev. 127, 481–489 (2006).
Ramos, B. P. et al. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40, 835–845 (2003).
Giralt, A. et al. Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington’s disease. Hum. Mol. Genet. 20, 4232–4247 (2011).
Hegde, S. et al. PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain. Neuroscience 335, 151–169 (2016).
Guo, S., Olesen, J. & Ashina, M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137, 2951–2959 (2014).
Holland, P. R. & Strother, L. Cilostazol as a chemically induced preclinical model of migraine. Cephalalgia 38, 415–416 (2018).
Khan, S., Deen, M., Hougaard, A., Amin, F. M. & Ashina, M. Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol. Cephalalgia 38, 892–903 (2018).
Hansen, E. K., Guo, S., Ashina, M. & Olesen, J. Toward a pragmatic migraine model for drug testing: I. Cilostazol in healthy volunteers. Cephalalgia 36, 172–178 (2016).
Birk, S., Kruuse, C., Petersen, K. A., Tfelt-Hansen, P. & Olesen, J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia 26, 1304–1309 (2006).
Mowat, F. M. et al. Gene therapy in a large animal model of PDE6A-retinitis pigmentosa. Front. Neurosci. 11, 342 (2017).
Henderson, D. J. et al. The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells. Br. J. Cancer 110, 1278–1287 (2014).
Abi-Gerges, A. et al. Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals. Circ. Res. 105, 784–792 (2009).
Wang, X., Ward, C. J., Harris, P. C. & Torres, V. E. Cyclic nucleotide signaling in polycystic kidney disease. Kidney Int. 77, 129–140 (2010).
Malekshahabi, T., Khoshdel Rad, N., Serra, A. L. & Moghadasali, R. Autosomal dominant polycystic kidney disease: disrupted pathways and potential therapeutic interventions. J. Cell. Physiol. 234, 12451–12470 (2019).
Zoraghi, R., Corbin, J. D. & Francis, S. H. Properties and functions of GAF domains in cyclic nucleotide phosphodiesterases and other proteins. Mol. Pharmacol. 65, 267–278 (2004).
Schultz, J. E. Structural and biochemical aspects of tandem GAF domains. Handb. Exp. Pharmacol. 191, 93–109 (2009).
Francis, S. H., Blount, M. A. & Corbin, J. D. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol. Rev. 91, 651–690 (2011).
Jager, R., Schwede, F., Genieser, H. G., Koesling, D. & Russwurm, M. Activation of PDE2 and PDE5 by specific GAF ligands: delayed activation of PDE5. Br. J. Pharmacol. 161, 1645–1660 (2010).
Martinez, S. E. et al. The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc. Natl Acad. Sci. USA 99, 13260–13265 (2002).
Beavo, J. A., Hardman, J. G. & Sutherland, E. W. Stimulation of adenosine 3΄,5΄-monophosphate hydrolysis by guanosine 3΄,5΄-monophosphate. J. Biol. Chem. 246, 3841–3846 (1971).
Jager, R. et al. Activation of PDE10 and PDE11 phosphodiesterases. J. Biol. Chem. 287, 1210–1219 (2012). This study is the first demonstration that PDEs can be pharmacologically activated by a molecule other than cAMP or cGMP itself (that is, PDE11A can be activated by a cGMP analogue binding the GAF-A domain).
D’Amours, M. R. & Cote, R. H. Regulation of photoreceptor phosphodiesterase catalysis by its non-catalytic cGMP-binding sites. Biochem. J. 340, 863–869 (1999).
Schultz, J. E., Dunkern, T., Gawlitta-Gorka, E. & Sorg, G. The GAF-tandem domain of phosphodiesterase 5 as a potential drug target. Handb. Exp. Pharmacol. 204, 151–166 (2011).
Kelly, M. P. Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target? Curr. Pharm. Des. 21, 389–416 (2015). This review introduces the unique idea that it may be possible to therapeutically target dual-specificity PDEs in a functionally selective manner (that is, target only their cAMP or cGMP hydrolytic activity).
Murthy, K. S., Zhou, H. & Makhlouf, G. M. PKA-dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle. Am. J. Physiol. Cell Physiol. 282, C508–C517 (2002).
Manganiello, V. C., Taira, M., Degerman, E. & Belfrage, P. Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family). Cell. Signal. 7, 445–455 (1995).
MacKenzie, S. J. et al. Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in upstream conserved region 1 (UCR1). Br. J. Pharmacol. 136, 421–433 (2002).
Corbin, J. D., Turko, I. V., Beasley, A. & Francis, S. H. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur. J. Biochem. 267, 2760–2767 (2000). This work is one of the first studies to identify phosphorylation as a PTM capable of changing PDE catalytic activity.
Brown, K. M., Lee, L. C., Findlay, J. E., Day, J. P. & Baillie, G. S. Cyclic AMP-specific phosphodiesterase, PDE8A1, is activated by protein kinase A-mediated phosphorylation. FEBS Lett. 586, 1631–1637 (2012).
Jacobitz, S., McLaughlin, M. M., Livi, G. P., Burman, M. & Torphy, T. J. Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding. Mol. Pharmacol. 50, 891–899 (1996).
Marcoz, P., Nemoz, G., Prigent, A. F. & Lagarde, M. Phosphatidic acid stimulates the rolipram-sensitive cyclic nucleotide phosphodiesterase from rat thymocytes. Biochim. Biophys. Acta 1176, 129–136 (1993).
Norambuena, A. et al. Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation. Mol. Biol. Cell 21, 2916–2929 (2010).
Grange, M. et al. The cAMP-specific phosphodiesterase PDE4D3 is regulated by phosphatidic acid binding. Consequences for cAMP signaling pathway and characterization of a phosphatidic acid binding site. J. Biol. Chem. 275, 33379–33387 (2000).
Wang, L. et al. UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy. Cell. Signal. 27, 908–922 (2015).
Guo, L. W. et al. The inhibitory gamma subunit of the rod cGMP phosphodiesterase binds the catalytic subunits in an extended linear structure. J. Biol. Chem. 281, 15412–15422 (2006).
Zhang, X. J., Skiba, N. P. & Cote, R. H. Structural requirements of the photoreceptor phosphodiesterase gamma-subunit for inhibition of rod PDE6 holoenzyme and for its activation by transducin. J. Biol. Chem. 285, 4455–4463 (2010).
Slep, K. C. et al. Structural determinants for regulation of phosphodiesterase by a G protein at 2.0 A. Nature 409, 1071–1077 (2001).
Zhang, Z. et al. Domain organization and conformational plasticity of the G protein effector, PDE6. J. Biol. Chem. 290, 12833–12843 (2015).
Lynch, M. J. et al. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J. Biol. Chem. 280, 33178–33189 (2005).
Ren, L. et al. MiR-541-5p regulates lung fibrosis by targeting cyclic nucleotide phosphodiesterase 1A. Exp. Lung Res. 43, 249–258 (2017).
Zhang, D. D., Li, Y., Xu, Y., Kim, J. & Huang, S. Phosphodiesterase 7B/microRNA-200c relationship regulates triple-negative breast cancer cell growth. Oncogene 38, 1106–1120 (2019).
Yang, G. et al. Phosphodiesterase 7A-deficient mice have functional T cells. J. Immunol. 171, 6414–6420 (2003).
Ding, B. et al. Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 111, 2469–2476 (2005).
Wu, W. H. et al. CRISPR repair reveals causative mutation in a preclinical model of retinitis pigmentosa. Mol. Ther. 24, 1388–1394 (2016). This work is a proof-of-concept study showing how gene editing might be used to therapeutically target a PDE.
Wensel, T. G. et al. Structural and molecular bases of rod photoreceptor morphogenesis and disease. Prog. Retin. Eye Res. 55, 32–51 (2016).
Deng, W. T. et al. Cone phosphodiesterase-6α’ restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-deficient rd10 mouse. J. Neurosci. 33, 11745–11753 (2013).
Pang, J. J. et al. AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEβ mutation. Invest. Ophthalmol. Vis. Sci. 49, 4278–4283 (2008). This work is one of the first studies showing that viral constructs can be used to therapeutically target a PDE.
Wert, K. J., Davis, R. J., Sancho-Pelluz, J., Nishina, P. M. & Tsang, S. H. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa. Hum. Mol. Genet. 22, 558–567 (2013).
Deng, W. T. et al. Cone phosphodiesterase-6γ’ subunit augments cone PDE6 holoenzyme assembly and stability in a mouse model lacking both rod and cone PDE6 catalytic subunits. Front. Mol. Neurosci. 11, 233 (2018).
Carvalho, L. S. et al. Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo. Hum. Gene Ther. 29, 771–784 (2018).
Ye, H. & Fussenegger, M. Optogenetic medicine: synthetic therapeutic solutions precision-guided by light. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a034371 (2018).
Yoshida, K., Tsunoda, S. P., Brown, L. S. & Kandori, H. A unique choanoflagellate enzyme rhodopsin exhibits light-dependent cyclic nucleotide phosphodiesterase activity. J. Biol. Chem. 292, 7531–7541 (2017).
Lamarche, L. B. et al. Purification and characterization of RhoPDE, a retinylidene/phosphodiesterase fusion protein and potential optogenetic tool from the choanoflagellate Salpingoeca rosetta. Biochemistry 56, 5812–5822 (2017). This work together with that of Yoshida et al. (2017) are the first studies to identify a light-dependent PDE with potential utility for optogenetic applications.
Tian, Y., Gao, S., Yang, S. & Nagel, G. A novel rhodopsin phosphodiesterase from Salpingoeca rosetta shows light-enhanced substrate affinity. Biochem. J. 475, 1121–1128 (2018).
Gasser, C. et al. Engineering of a red-light-activated human cAMP/cGMP-specific phosphodiesterase. Proc. Natl Acad. Sci. USA 111, 8803–8808 (2014).
Kelly, M. P. Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain. Cell. Signal. 42, 281–291 (2018). This review underscores the fact that any targeting of PDE activity in the context of age-related disease will likely need to be done in a tissue-specific manner, as some tissues see increased cyclic nucleotide signalling with age whereas others see decreased signalling.
Fertig, B. A. & Baillie, G. S. PDE4-mediated cAMP signalling. J. Cardiovasc. Dev. Dis. 5, E8 (2018).
McCahill, A. et al. In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region. Cell. Signal. 17, 1158–1173 (2005).
Bolger, G. B. et al. Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5. Biochem. J. 398, 23–36 (2006). This work is a first report of a key technique in the field (that is, the scanning peptide array) that has been successfully used to identify many PDE protein–protein binding partners.
Baillie, G. S. et al. β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from Gs to Gi. Proc. Natl Acad. Sci. USA 100, 940–945 (2003). This work presents a seminal finding showing how PDEs can trigger negative feedback loops upstream (that is, by making a receptor switch from Gs to Gi signalling).
Willoughby, D. et al. Dynamic regulation, desensitization, and cross-talk in discrete subcellular microdomains during beta2-adrenoceptor and prostanoid receptor cAMP signaling. J. Biol. Chem. 282, 34235–34249 (2007).
Ong, W. K. et al. The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release. Br. J. Pharmacol. 157, 633–644 (2009).
Terrin, A. et al. PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome. J. Cell Biol. 198, 607–621 (2012).
Vecsey, C. G. et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461, 1122–1125 (2009).
Havekes, R. et al. Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1. eLife 5, e13424 (2016).
Havekes, R. et al. Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory. J. Neurosci. 36, 8936–8946 (2016).
Campbell, S. L., van Groen, T., Kadish, I., Smoot, L. H. M. & Bolger, G. B. Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus. BMC Neurosci. 18, 77 (2017).
McGirr, A. et al. Specific inhibition of phosphodiesterase-4B results in anxiolysis and facilitates memory acquisition. Neuropsychopharmacology 41, 1080–1092 (2016).
Johnston, L. A. et al. Expression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene. Biochem. J. 380, 371–384 (2004). This report identifies a catalytically dead isoform of PDE4A, showing that nature has developed its own dominant-negative approach.
Lynch, M. J., Baillie, G. S. & Houslay, M. D. cAMP-specific phosphodiesterase-4D5 (PDE4D5) provides a paradigm for understanding the unique non-redundant roles that PDE4 isoforms play in shaping compartmentalized cAMP cell signalling. Biochem. Soc. Trans. 35, 938–941 (2007).
Wills, L., Ehsan, M., Whiteley, E. L. & Baillie, G. S. Location, location, location: PDE4D5 function is directed by its unique N-terminal region. Cell. Signal. 28, (701–705 (2016).
Yun, S. et al. Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nat. Cell Biol. 18, 1043–1053 (2016).
Ahmad, F. et al. Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. J. Biol. Chem. 290, 6763–6776 (2015).
Lee, L. C., Maurice, D. H. & Baillie, G. S. Targeting protein–protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Med. Chem. 5, 451–464 (2013).
Delyon, J. et al. PDE4D promotes FAK-mediated cell invasion in BRAF-mutated melanoma. Oncogene 36, 3252–3262 (2017).
Serrels, B. et al. A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity. Curr. Biol. 20, 1086–1092 (2010).
Martin, T. P. et al. Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy. FEBS Open Bio 4, 923–927 (2014).
Keravis, T. & Lugnier, C. Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr. Pharm. Des. 16, 1114–1125 (2010).
MacMullen, C. M., Vick, K., Pacifico, R., Fallahi-Sichani, M. & Davis, R. L. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder. Transl Psychiatry 6, e742 (2016).
Movsesian, M. Novel approaches to targeting PDE3 in cardiovascular disease. Pharmacol. Ther. 163, 74–81 (2016).
Kotera, J. et al. Subcellular localization of cyclic nucleotide phosphodiesterase type 10A variants, and alteration of the localization by cAMP-dependent protein kinase-dependent phosphorylation. J. Biol. Chem. 279, 4366–4375 (2004).
Russwurm, C., Koesling, D. & Russwurm, M. Phosphodiesterase 10A is tethered to a synaptic signaling complex in striatum. J. Biol. Chem. 290, 11936–11947 (2015).
Kelly, M. P. A. Role for phosphodiesterase 11A (PDE11A) in the formation of social memories and the stabilization of mood. Adv. Neurobiol. 17, 201–230 (2017).
Carlisle Michel, J. J. et al. PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. Biochem. J. 381, 587–592 (2004).
Suryavanshi, S. V. et al. Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling. Am. J. Physiol. Heart Circ. Physiol. 315, H109–H121 (2018).
Zhu, H. et al. Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. Mol. Cell. Biol. 30, 4379–4390 (2010).
VerPlank, J. J. S. & Goldberg, A. L. Regulating protein breakdown through proteasome phosphorylation. Biochem. J. 474, 3355–3371 (2017).
Cai, Y. et al. Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition. Biochim. Biophys. Acta Mol. Cell Res. 1865, 297–308 (2018).
Li, X., Baillie, G. S. & Houslay, M. D. Mdm2 directs the ubiquitination of beta-arrestin-sequestered cAMP phosphodiesterase-4D5. J. Biol. Chem. 284, 16170–16182 (2009). This study is the first to identify a PTM that regulates PDE signalling via degradation.
Li, X. et al. Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK. Biochem. J. 428, 55–65 (2010).
Hay, R. T. Decoding the SUMO signal. Biochem. Soc. Trans. 41, 463–473 (2013).
Hoffmann, R., Baillie, G. S., MacKenzie, S. J., Yarwood, S. J. & Houslay, M. D. The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. EMBO J. 18, 893–903 (1999).
Wang, Y. et al. S-Nitrosylation of PDE5 increases its ubiquitin-proteasomal degradation. Free Radic. Biol. Med. 86, 343–351 (2015).
Garcia, J. A. Aiming straight for the heart: prolyl hydroxylases set the BAR. Sci. Signal. 2, e70 (2009).
Huo, Z. et al. Prolyl hydroxylase domain protein 2 regulates the intracellular cyclic AMP level in cardiomyocytes through its interaction with phosphodiesterase 4D. Biochem. Biophys. Res. Commun. 427, 73–79 (2012).
Lorenz, R., Bertinetti, D. & Herberg, F. W. cAMP-dependent protein kinase and cGMP-dependent protein kinase as cyclic nucleotide effectors. Handb. Exp. Pharmacol. 238, 105–122 (2017).
VanSchouwen, B. & Melacini, G. Regulation of HCN ion channels by non-canonical cyclic nucleotides. Handb. Exp. Pharmacol. 238, 123–133 (2017).
Rehmann, H. Interaction of Epac with non-canonical cyclic nucleotides. Handb. Exp. Pharmacol. 238, 135–147 (2017).
Hauser, A. R. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat. Rev. Microbiol. 7, 654–665 (2009).
Wolter, S. et al. cCMP causes caspase-dependent apoptosis in mouse lymphoma cell lines. Biochem. Pharmacol. 98, 119–131 (2015).
Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019).
Liu, F. C. et al. Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge. J. Nanobiotechnol. 16, 35 (2018).
Yu, S. et al. Targeted delivery of an anti-inflammatory PDE4 inhibitor to immune cells via an antibody-drug conjugate. Mol. Ther. 24, 2078–2089 (2016).
Raymond, D. R., Wilson, L. S., Carter, R. L. & Maurice, D. H. Numerous distinct PKA-, or EPAC-based, signalling complexes allow selective phosphodiesterase 3 and phosphodiesterase 4 coordination of cell adhesion. Cell. Signal. 19, 2507–2518 (2007).
Sapio, L. et al. Targeting protein kinase A in cancer therapy: an update. EXCLI J. 13, 843–855 (2014).
Raker, V. K., Becker, C. & Steinbrink, K. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front. Immunol. 7, 123 (2016).
Kumar, N. et al. Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment. Mol. Cell Biochem. 447, 77–92 (2018).
Parnell, E., Palmer, T. M. & Yarwood, S. J. The future of EPAC-targeted therapies: agonism versus antagonism. Trends Pharmacol. Sci. 36, 203–214 (2015).
Holland, N. A. et al. Cyclic nucleotide-directed protein kinases in cardiovascular inflammation and growth. J. Cardiovasc. Dev. Dis. 5, E6 (2018).
Kleppe, R., Krakstad, C., Selheim, F., Kopperud, R. & Doskeland, S. O. The cAMP-dependent protein kinase pathway as therapeutic target: possibilities and pitfalls. Curr. Top. Med. Chem. 11, 1393–1405 (2011).
Bollen, E. et al. Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. Neuropsychopharmacology 39, 2497–2505 (2014).
Joshi, R. et al. Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway. Mol. Cell. Endocrinol. 393, 152–163 (2014).
Miller, C. L. et al. Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Bas. Res. Cardiol. 106, 1023–1039 (2011).
Zhang, H. T. et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27, 587–595 (2002).
Salpietro, V. et al. A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Mov Disord. 33, 482–488 (2018).
Iribarne, M. & Masai, I. Neurotoxicity of cGMP in the vertebrate retina: from the initial research on rd mutant mice to zebrafish genetic approaches. J. Neurogenet. 31, 88–101 (2017).
Savai, R. et al. Targeting cancer with phosphodiesterase inhibitors. Expert Opin. Investig. Drugs 19, 117–131 (2010).
Ahmad, F. et al. Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis. 21, e25–e50 (2015).
Zuo, H., Cattani-Cavalieri, I., Musheshe, N., Nikolaev, V. O. & Schmidt, M. Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacol. Ther. 197, 225–242 (2019).
Pincelli, C., Schafer, P. H., French, L. E., Augustin, M. & Krueger, J. G. Mechanisms underlying the clinical effects of apremilast for psoriasis. J. Drugs Dermatol. 17, 835–840 (2018).
Gupta, A., Tiwari, M., Prasad, S. & Chaube, S. K. Role of cyclic nucleotide phosphodiesterases during meiotic resumption from diplotene arrest in mammalian oocytes. J. Cell. Biochem. 118, 446–452 (2017).
Drobnis, E. Z. & Nangia, A. K. Phosphodiesterase inhibitors (PDE inhibitors) and male reproduction. Adv. Exp. Med. Biol. 1034, 29–38 (2017).
Vasta, V. et al. Identification of a new variant of PDE1A calmodulin-stimulated cyclic nucleotide phosphodiesterase expressed in mouse sperm. Biol. Reprod. 73, 598–609 (2005).
Alves de Inda, M. et al. Validation of cyclic adenosine monophosphate phosphodiesterase-4D7 for its independent contribution to risk stratification in a prostate cancer patient cohort with longitudinal biological outcomes. Eur. Urol. Focus 4, 376–384 (2018).
van Strijp, D. et al. The prognostic PDE4D7 score in a diagnostic biopsy prostate cancer patient cohort with longitudinal biological outcomes. Prostate Cancer 2018, 5821616 (2018).
Bottcher, R. et al. Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression. Br. J. Cancer 113, 1502–1511 (2015). This work is the first of three key studies (see the two additional studies by Alves de India  and van Strijp ) that led to the development of a PDE4D7-based prostate cancer biomarker.
Bottcher, R. et al. Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases. Oncotarget 7, 70669–70684 (2016).
MDxHealth. MDxHealth launch agreement with Philips for prognostic prostate cancer biomarker. MDxHealth https://mdxhealth.com/press-release/mdxhealth-launch-agreement-philips-prognostic-prostate-cancer-biomarker (2018).
Nazir, M. et al. Targeting tumor cells based on phosphodiesterase 3A expression. Exp. Cell Res. 361, 308–315 (2017).
Vandenberghe, P. et al. Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST). Oncotarget 8, 41026–41043 (2017).
Fryknas, M. et al. Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model. J. Biomol. Screen 11, 457–468 (2006).
Ahmad, R. et al. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology 82, 279–281 (2014).
Wilson, H. et al. Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington’s disease gene carriers. J. Neurol. Sci. 368, 243–248 (2016).
Niccolini, F. et al. Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson’s disease. Brain 138, 3003–3015 (2015). This work is an important study showing how in vivo imaging of a PDE may prove a useful biomarker for disease diagnosis and monitoring.
Schroder, S., Wenzel, B., Deuther-Conrad, W., Scheunemann, M. & Brust, P. Novel radioligands for cyclic nucleotide phosphodiesterase imaging with positron emission tomography: an update on developments since 2012. Molecules 21, E650 (2016).
Neves, S. R., Ram, P. T. & Iyengar, R. G protein pathways. Science 296, 1636–1639 (2002).
Chen, J., Martinez, J., Milner, T. A., Buck, J. & Levin, L. R. Neuronal expression of soluble adenylyl cyclase in the mammalian brain. Brain Res. 1518, 1–8 (2013).
Kobialka, M. & Gorczyca, W. A. Particulate guanylyl cyclases: multiple mechanisms of activation. Acta Biochim. Pol. 47, 517–528 (2000).
Brand, T. The Popeye domain containing genes and their function as cAMP effector proteins in striated muscle. J. Cardiovasc. Dev. Dis. 5, E18 (2018).
Gamanuma, M. et al. Comparison of enzymatic characterization and gene organization of cyclic nucleotide phosphodiesterase 8 family in humans. Cell. Signal. 15, 565–574 (2003).
Goraya, T. A. & Cooper, D. M. Ca2+-calmodulin-dependent phosphodiesterase (PDE1): current perspectives. Cell. Signal. 17, 789–797 (2005).
Pandit, J., Forman, M. D., Fennell, K. F., Dillman, K. S. & Menniti, F. S. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc. Natl Acad. Sci. USA 106, 18225–18230 (2009). This seminal work reveals the three-dimensional nature by which cyclic nucleotide binding and protein–protein interactions at a PDE GAF domain can influence the ability of the regulatory N-terminal to control access of the catalytic pocket.
Qureshi, B. M. et al. It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods. Open Biol. 8, 180075 (2018).
Francis, S. H., Houslay, M. D. & Conti, M. Phosphodiesterase inhibitors: factors that influence potency, selectivity, and action. Handb. Exp. Pharmacol. 204, 47–84 (2011).
Berthouze-Duquesnes, M. et al. Specific interactions between Epac1, beta-arrestin2 and PDE4D5 regulate beta-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling. Cell. Signal. 25, 970–980 (2013).
Bolger, G. B. RACK1 and beta-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5. Cell. Signal. 28, 706–712 (2016).
Govindan, R. et al. A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104. J. Thorac. Oncol. 4, 220–226 (2009).
Dawson, N. A. et al. A phase II study of estramustine, docetaxel, and exisulind in patients with hormone-refractory prostate cancer: results of cancer and leukemia group B trial 90004. Clin. Genitourin. Cancer 6, 110–116 (2008).
Yu, E. Y. et al. A pilot study of high-dose exisulind in men with biochemical relapse (BCR) of prostate cancer after definitive local therapy treated with intermittent androgen deprivation (IAD). J. Clin. Oncol. 31, 209–209 (2013).
Curiel-Lewandrowski, C. et al. Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma: evaluation of potential chemopreventive activity. Cancer 118, 5848–5856 (2012).
Leung, D. G. et al. Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann. Neurol. 76, 541–549 (2014).
Victor, R. G. et al. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Neurology 89, 1811–1820 (2017).
McDonald, C. M. et al. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 41, 500–510 (2010).
Ramirez, C. E. et al. Treatment with sildenafil improves insulin sensitivity in prediabetes: a randomized, controlled trial. J. Clin. Endocrinol. Metab. 100, 4533–4540 (2015).
Frolich, L. et al. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer’s disease. Alzheimers Res. Ther. 11, 18 (2019).
Targum, S. D. et al. Application of external review for subject selection in a schizophrenia trial. J. Clin. Psychopharmacol. 32, 825–826 (2012).
Targum, S. D. et al. Impact of BPRS interview length on ratings reliability in a schizophrenia trial. Eur. Neuropsychopharmacol. 25, 312–318 (2015).
Delnomdedieu, M. et al. In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects. Neuropharmacology 117, 171–181 (2017). This study is an example of how clinical trials are attempting to verify target engagement when testing PDE inhibitors in the context of nervous system disorders.
Metz, V. E. et al. Effects of ibudilast on the subjective, reinforcing, and analgesic effects of oxycodone in recently detoxified adults with opioid dependence. Neuropsychopharmacology 42, 1825–1832 (2017).
Zhang, F. et al. Vinpocetine inhibits NF-κB-dependent inflammation in acute ischemic stroke patients. Transl Stroke Res. 9, 174–184 (2018).
Ma, X. W. et al. A randomized, open-label, multicentre study to evaluate plasma atherosclerotic biomarkers in patients with type 2 diabetes mellitus and arteriosclerosis obliterans when treated with probucol and cilostazol. J. Geriatr. Cardiol. 9, 228–236 (2012).
Lee, J. Y. et al. Efficacy of cilostazol administration in Alzheimer’s disease patients with white matter lesions: a positron-emission tomography study. Neurotherapeutics 16, 394–403 (2019).
Heckman, P. R. A. et al. Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial. Psychopharmacology 235, 301–308 (2018).
Wouters, E. F. et al. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 97, E1720–E1725 (2012).
Gonzalez-Ortiz, M., Martinez-Abundis, E., Hernandez-Corona, D. M. & Ramirez-Rodriguez, A. M. Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men. Acta Clin. Belg. 72, 326–330 (2017).
Sbardella, E. et al. Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas. Eur. J. Endocrinol. 178, 501–511 (2018).
Pauls, M. M. H. et al. Perfusion by arterial spin labelling following single dose tadalafil in small vessel disease (PASTIS): study protocol for a randomised controlled trial. Trials 18, 229 (2017).
Charnigo, R. J. et al. PF-04447943, a phosphodiesterase 9A inhibitor, in stable sickle cell disease patients: a phase Ib randomized, placebo-controlled study. Clin. Transl Sci. 12, 180–188 (2019).
Moschetti, V. et al. First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males. Br. J. Clin. Pharmacol. 82, 1315–1324 (2016).
Boland, K. et al. A phase I, randomized, proof-of-clinical-mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers. Hum. Psychopharmacol. 32, e2569 (2017).
Fazio, P. et al. Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: a PET study with (18)F-MNI-659 and (11)C-raclopride with correction for partial volume effect. Neuroimage 152, 330–339 (2017).
Work supported by 1R01MH101130 and 1R01AG061200 (M.P.K.). G.S.B. is supported by grants from the British Heart Foundation (BHF/TARGETPDE/PG/17/26/32881) and Medical Research Council (MC-PC-13063 and MC-PC-15039). G.S.T. is a fellow of the AstraZeneca postdoctoral programme.
G.S.B. is co-founder and director of Portage Glasgow Limited. The other authors declare no competing interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Subcellular compartments within which intracellular signalling is discretely localized largely due to anchoring of molecules within macromolecular complexes.
A rare congenital disorder characterized by abnormal bone growth leading to very short fingers/toes, underdeveloped facial bones, a small nose and short stature, as well as developmental and intellectual disabilities.
- Cerebral hypofusion
Reduces blood flow to/throughout the brain.
- Coronary stent stenosis
A gradual re-narrowing of a coronary artery leading to restricted blood flow that occurs after angioplasty and stenting have been performed to relieve a prior blockage.
A movement disorder characterized by repetitive or twisting movements due to involuntary muscle contraction.
- Lichen planus
An inflammatory condition characterized by purplish, itchy bumps on/around the skin, hair, nails and mucous membrane (due to unknown causes).
Diminished voluntary movements or uncontrollable involuntary movements (for example, tics or chorea).
- Retinitis pigmentosa
A rare genetic disorder characterized by black pigmentation and retinal degeneration.
The process whereby the regulatory domains from one phosphodiesterase (PDE) enzyme physically bind — and, thus, block substrate access to — the C-terminal catalytic domain of another PDE molecule.
A phosphorylation motif that alters the rate of degradation by attracting ubiquitin ligases to the phosphorylated protein.
About this article
Cite this article
Baillie, G.S., Tejeda, G.S. & Kelly, M.P. Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond. Nat Rev Drug Discov 18, 770–796 (2019). https://doi.org/10.1038/s41573-019-0033-4
Inhibition of PDE4 by apremilast attenuates skin fibrosis through directly suppressing activation of M1 and T cells
Acta Pharmacologica Sinica (2021)
Photoreceptor phosphodiesterase (PDE6): activation and inactivation mechanisms during visual transduction in rods and cones
Pflügers Archiv - European Journal of Physiology (2021)
An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
Nature Communications (2020)
Naunyn-Schmiedeberg's Archives of Pharmacology (2020)