PDE4 inhibitor explained

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.^[1]

Therapeutic utility

The prototypical PDE4 inhibitor is rolipram. PDE4 inhibitors are known to possess procognitive (including long term memory-improving),^[2] wakefulness-promoting,^[3] neuroprotective,^{[4] [5]} and anti-inflammatory effects.^[6] Consequently, PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), anxiety disorders, schizophrenia,^{[7] [8]} Parkinson's disease,^[9] Alzheimer's disease,^[10] multiple sclerosis,^[11] attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.^{[12] [13] [14]}

PDE4D inhibition, along with PDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.^[14] Similarly PDE4B inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors,^[13] in line with this view PDE4B polymorphisms and altered gene expression in the central nervous system have been associated with schizophrenia and bipolar disorder in a postmortem study.^[15] PDE4 also regulates the D₁/PKA/DARPP-32 signalling cascade in the frontal cortex, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.^[16] Whereas PDE4C is expressed primarily in the periphery and hence may be partly responsible for the peripheral effects of PDE4 inhibitors (e.g. their anti-inflammatory effects).^[14] PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats,^[17] hence suggesting its possible utility in the treatment of alcohol dependence. Indeed, one experiment has found that intake of a PDE4 oral medication for psoriasis has significantly reduced alcohol consumption in serious human drinkers compared with those taking the placebo.^[18] A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.^[19]

The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects, which appear to be related to their inhibition of PDE4D which is expressed in the area postrema.^[14]

Adverse reactions

Nausea, vomiting, and related general gastrointestinal side effects are the most commonly implicated side effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections, which have been discovered from the clinical use of roflumilast.^[20]

Examples

See also: List of phosphodiesterase inhibitors.

• Apremilast, a phthalimide derivative that was approved by the U.S. FDA in March 2014 for use as a treatment for psoriatic arthritis,^[21] and in September 2014 for the treatment of plaque psoriasis under the brand name Otezla.^[22]
• Cilomilast, in clinical development by GlaxoSmithKline for treatment of COPD.^[23]
• Crisaborole (AN2728), a boron-containing drug for the topical treatment of psoriasis and atopic dermatitis.^{[24] [25]} It was approved by the FDA on December 14, 2016 under the brand name Eucrisa for the treatment of mild-to-moderate atopic dermatitis (eczema) in patients 2 years of age and older.^[26]
• Caffeine is a weak, non-selective PDE inhibitor.^[27] A metabolite of caffeine, theophylline, is a more potent PDE inhibitor.
• Diazepam, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant.^[28]
• Glaucine, an aporphine alkaloid, low-potency PDE4 inhibitor, calcium channel blocker, dopamine antagonist and 5-HT2A positive allosteric modulator, used as antitussive in Eastern Europe and Iceland.
• Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose.
• Luteolin, supplement extracted from peanuts and other plants that also possesses IGF-1 properties.^[29]
• Mesembrenone, an alkaloid from the herb Sceletium tortuosum (Kanna).
• Piclamilast, a more potent inhibitor than rolipram.^[30]
• Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU, Russia and U.S. by Merck & Co. under the trade names Daxas^[20] and Daliresp, and for the treatment of plaque psoriasis under the brand name Zoryve.^[31]
• Rolipram, used as investigative tool in pharmacological research.
• Mesembrine, an alkaloid present in Sceletium tortuosum (kanna).

Mode of action

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

See also

• Development of analogs of thalidomide
• Forskolin

Notes and References

1. 10.1038/bjp.2008.307. PDE4 inhibitors: current status. British Journal of Pharmacology. 2008. D. Spina. 155. 3. 308–315. 18660825. 2567892.
2. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E . Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory . Proceedings of the National Academy of Sciences of the United States of America . 1998 . 15020 - 5 . 95 . 25 . 9844008 . 24568 . 10.1073/pnas.95.25.15020. 1998PNAS...9515020B . free .
3. Lelkes Z, Alföldi P, Erdos A, Benedek G . Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats . Pharmacology Biochemistry and Behavior . 1998 . 835 - 9 . 60 . 4 . 9700966 . 10.1016/S0091-3057(98)00038-0. 37020086 .
4. Block F, Schmidt W, Nolden-Koch M, Schwarz M . Rolipram reduces excitotoxic neuronal damage . NeuroReport . 2001 . 1507 - 11 . 12 . 7 . 11388438 . 10.1097/00001756-200105250-00041. 2768440 .
5. Chen RW, Williams AJ, Liao Z, Yao C, Tortella FC, Dave JR . Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation . Neuroscience Letters . 2007 . 165 - 9 . 418 . 2 . 17398001 . 10.1016/j.neulet.2007.03.033. 25453633 .
6. Web site: Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators . 2012-07-24 . 2012 . Celgene Corporation . 2019-08-13 . https://web.archive.org/web/20190813003524/http://www.discoverpde4.com/intracellular-mechanisms.html . dead .
7. Maxwell CR, Kanes SJ, Abel T, Siegel SJ . Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications . Neuroscience . 2004 . 101–7 . 129 . 1 . 15489033 . 10.1016/j.neuroscience.2004.07.038. 19578277 .
8. 10.1016/j.neuroscience.2006.09.026 . Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP . Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity . Neuroscience . 2006 . 239–246 . 144 . 1 . 17081698 . 3313447.
9. Web site: Oxidative Damage in Parkinson's Disease . https://web.archive.org/web/20120523193305/http://handle.dtic.mil/100.2/ADA434051 . dead . May 23, 2012 . MF . Beal . Cleren, C . Calingasan, NY . Yang, L . Klivenyi, P . Lorenzl, S . 2005 . U.S. Army Medical Research and Material Command Fort Detrick, Maryland 21702-5012 .
10. Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proceedings of the National Academy of Sciences of the United States of America. September 2009. DL. Smith. Pozueta, J . Gong, B . Arancio, O . Shelanski, M . 106. 39. 16877–16882. 19805389. 2743726. 10.1073/pnas.0908706106 . 2009PNAS..10616877S . free.
11. Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis?. BioDrugs. February 2000. 13. 2. 87–94. Dinter, H. 18034515. 10.2165/00063030-200013020-00002. 23444101.
12. Update on the therapeutic potential of PDE4 inhibitors. Expert Opinion on Investigational Drugs. January 2002. 11. 1. 1–13. 10.1517/13543784.11.1.1. 11772317. Dyke, HJ . Montana, JG . 22623399.
13. PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia?. Drug Discovery Today. 12. 19–20. October 2007. 870–878. 10.1016/j.drudis.2007.07.023. Halene, TB . Siegel, SJ . 17933689.
14. Book: Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology. 204. 2011. 10.1007/978-3-642-17969-3. 978-3-642-17968-6. Springer Berlin Heidelberg. Francis, SH . Conti, M . Houslay, MD.
15. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophrenia Research. 101. 1–3. 10.1016/j.schres.2008.01.029. 18394866. 36–49. Fatemi, SH . King, DP . Reutiman, TJ . Folsom, TD . Laurence, JA . Lee, S . Fan, YT . Paciga, SA . Conti, M . Menniti, FS . April 2008. 32661995.
16. Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology. February 2012. 219. 4. 1065–1079. 10.1007/s00213-011-2436-8. 21833500. 3539205. Kuroiwa, M . Snyder, GL . Shuto, T . Fukuda, A . Yanagawa, Y . Benavides, DR . Nairn, AC . Bibb, JA . Greengard, P . Nishi, A .
17. The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-Preferring Fawn-Hooded Rats. Alcoholism: Clinical and Experimental Research. December 2012. 10.1111/j.1530-0277.2012.01845.x. 22671516. 36. 12. 2157–2167. Wen, RT . Zhang, M . Qin, WJ . Liu, Q . Wang, WP . Lawrence, AJ . Zhang, HT . Liang, JH . 4335658.
18. Wilson, C. (2021). Psoriasis drug may cut alcohol misuse. New Scientist, 250(3340), p.16
19. Treating brain tumors with PDE4 inhibitors. Trends in Pharmacological Sciences. June 2011. 32. 6. 337–344. 10.1016/j.tips.2011.02.015. 21450351. 3106141. Sengupta, R . Sun, T . Warrington, NM . Rubin, JB .
20. Web site: DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]]. August 2013. 13 November 2013. DailyMed. Forest Laboratories, Inc..
21. News: FDA Clears Apremilast (Otezla) for Psoriatic Arthritis. Medscape Medical News. WebMD. 28 March 2014. Brooks, M. 21 March 2014.
22. News: FDA Approves Apremilast (Otezla) for Plaque Psoriasis. Medscape Medical News. WebMD. 13 October 2014. Lowes, R. 23 September 2014.
23. The efficacy and safety of cilomilast in COPD. Drugs. 2008. 68. Suppl 2. 3–57. Rennard, S . Knobil, K . Rabe, KF . Morris, A . Schachter, N . Locantore, N . Canonica, WG . Zhu, Y . Barnhart, F . 10.2165/0003495-200868002-00002. 19105585. 2216800.
24. Nazarian . R . Weinberg . JM . AN-2728, a PDE4 Inhibitor for the Potential Topical Treatment of Psoriasis and Atopic Dermatitis . Current Opinion in Investigational Drugs . November 2009 . 10 . 11 . 1236–42 . 19876791.
25. Moustafa . F . Feldman . SR . A Review of Phosphodiesterase-Inhibition and the Potential Role for Phosphodiesterase 4-Inhibitors in Clinical Dermatology . Dermatology Online Journal . 16 May 2014 . 20 . 5 . 22608 . 10.5070/D3205022608 . 24852768 . free .
26. Web site: FDA Approves Eucrisa for Eczema . U.S. Food and Drug Administration . 14 December 2016.
27. Boswell-Smith . Victoria . Spina . Domenico . Page . Clive P. . January 2006 . Phosphodiesterase inhibitors . British Journal of Pharmacology . 147 . Suppl 1 . S252–257 . 10.1038/sj.bjp.0706495 . 0007-1188 . 1760738 . 16402111.
28. Collado, M. C. . Beleta, J. . Martinez, E. . Miralpeix, M. . Domènech, T. . Palacios, J. M. . Hernández, J. . 1998 . Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor . British Journal of Pharmacology . 123 . 6 . 1047–1054 . 9559885 . 1565256 . 10.1038/sj.bjp.0701698 .
29. Yu, M. C. . Chen, J. H. . Lai, C. Y. . Han, C. Y. . Ko, W. C. . Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [(3)H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia . European Journal of Pharmacology . 2009 . 269–275 . 627 . 1–3 . 19853596 . 10.1016/j.ejphar.2009.10.031.
30. de Visser, Y. P. . Walther, F. J. . Laghmani E. H. . van Wijngaarden, S. . Nieuwland, K. . Wagenaar, G. T. . Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury . European Respiratory Journal . 2008 . 633–644 . 31 . 3 . 18094015 . 10.1183/09031936.00071307 . free .
31. FDA Approves Arcutis' Zoryve (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis in Individuals Age 12 and Older . Arcutis Biotherapeutics . GlobeNewswire . 29 July 2022 . 1 August 2022 . 1 August 2022 . https://web.archive.org/web/20220801114445/https://www.globenewswire.com/news-release/2022/07/29/2488966/0/en/FDA-Approves-Arcutis-ZORYVE-Roflumilast-Cream-0-3-For-the-Treatment-of-Plaque-Psoriasis-in-Individuals-Age-12-and-Older.html . live .