Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs): Introduction

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PDE4
PDE4 isoenzymes are encoded by four genes (A-D). Alternate transcripts of each gene give rise to a large number of enzyme variants. PDE4s hydrolyze the second messenger, cAMP. PDE4 is a major subtype of PDEs expressed by immune or inflammatory cells.
Three cAMP-specific PDEs are found in human neutrophils, PDE3, PDE4, and PDE7. PDE4 was identified as a tractable molecular target for the development of anti-inflammatory drugs with a mechanism of action distinct from that of the glucocortocoids [8]. Since the late 1980s the pharmaceutical industry has been searching for suitable inhibitor compounds with the potential to treat a wide range of inflammatory and non-inflammatory conditions, that would be likely to respond to elevated cAMP levels [3-5,7]. To date, two PDE4-selective inhibitors have received marketing authorisation in either the US and/or the EU: roflumilast (for asthma and chronic obstructive pulmonary disease) and apremilast (for psoriatic arthritis and moderate to severe plaque psoriasis). The use of PDE4 inhibitors is plagued by dose-limiting adverse events, including nausea, diarrhoea, abdominal pain, vomiting and dyspepsia. Inhibition of PDE4D isozymes in non-target tissues is believed to cause the emetic effects, whilst inhibition of PDE4A and/or PDE4B in pro-inflammatory and immune cells is believed produce the desired therapeutic effects [2]. Inhibitors with increased selectivity for PDE4A/4B over PDE4D would therefore be likely solve the emetic adverse effects problem, although so far this challenge has been largely unmet by the medicinal chemists. Inhibition of PDE4B by the PDE4 inhibitor rolipram induces antipsychotic effects [6], and inhibition of this isoform may have clinical potential for enhancing cognition and memory. Crisaborole, a pan-PDE inhibitor exhibits limited selectivity for PDE4B [1].

References

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1. Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg. Med. Chem. Lett., 19 (8): 2129-32. [PMID:19303290]

2. Giembycz MA. (2008) Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?. Br. J. Pharmacol., 155 (3): 288-90. [PMID:18660832]

3. Giembycz MA, Newton R. (2011) Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. Handb Exp Pharmacol, (204): 415-46. [PMID:21695651]

4. Keshavarzian A, Mutlu E, Guzman JP, Forsyth C, Banan A. (2007) Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease. Expert Opin Investig Drugs, 16 (9): 1489-506. [PMID:17714033]

5. Mulhall AM, Droege CA, Ernst NE, Panos RJ, Zafar MA. (2015) Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. Expert Opin Investig Drugs, 24 (12): 1597-611. [PMID:26419847]

6. Porteous DJ, Millar JK, Brandon NJ, Sawa A. (2011) DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol Med, 17 (12): 699-706. [PMID:22015021]

7. Salari-Sharif P, Abdollahi M. (2010) Phosphodiesterase 4 inhibitors in inflammatory bowel disease: a comprehensive review. Curr. Pharm. Des., 16 (33): 3661-7. [PMID:21128899]

8. Torphy TJ, Undem BJ. (1991) Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax, 46 (7): 512-23. [PMID:1877039]

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Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs), introduction. Last modified on 03/04/2018. Accessed on 21/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=260.