phosphodiesterase inhibitor

The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s{{cite journal | pmid = 4321663 | volume=10 | title=Multiple cyclic nucleotide phosphodiesterase activities from rat brain | year=1971 | journal=Biochemistry | pages=311–6 | vauthors=Thompson WJ, Appleman MM| issue=2 | doi=10.1021/bi00778a018 }}{{cite journal |author1=Uzunov P. |author2=Weiss B. | year = 1972 | title = Separation of multiple molecular forms of cyclic adenosine 3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis | journal = Biochim. Biophys. Acta | volume = 284 | issue = 1| pages = 220–226 | doi = 10.1016/0005-2744(72)90060-5 | pmid=4342220}} and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs.{{cite journal | author = Weiss B | year = 1975 | title = Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase | journal = Adv. Cycl. Nucl. Res. | volume = 5 | pages = 195–211 | pmid = 165666 }}{{cite journal | vauthors = Fertel R, Weiss B | year = 1976 | title = Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung | journal = Mol. Pharmacol. | volume = 12 | issue = 4| pages = 678–687 | pmid = 183099 }} The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait.{{cite journal |author1=Weiss B. |author2=Hait W.N. | year = 1977 | title = Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 17 | pages = 441–477 | doi=10.1146/annurev.pa.17.040177.002301 | pmid=17360}} This prediction meanwhile has proved to be true in a variety of fields.

{{See also|List of phosphodiesterase inhibitors}}

Methylated xanthines and derivatives:{{cite journal | author=Essayan DM. | title=Cyclic nucleotide phosphodiesterases. | journal=The Journal of Allergy and Clinical Immunology | year=2001 | pages=671–80 | volume=108 | issue=5 | pmid=11692087 | doi=10.1067/mai.2001.119555 | doi-access=free }}

• caffeine, a minor stimulant
• aminophylline
• IBMX (3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research
• paraxanthine
• pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries{{cite journal | vauthors=Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R | title=Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition | journal=Clinics (Sao Paulo) | year=2008 | pages=321–8 | volume=63 | issue=3 | pmid=18568240 | doi=10.1590/S1807-59322008000300006 | pmc=2664230 }}
• theobromine
• theophylline, a bronchodilator

Methylated xanthines act as both

1. competitive nonselective phosphodiesterase inhibitors, which raise intracellular cAMP, activate PKA, inhibit TNF-alpha{{cite journal |vauthors =Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U |title=Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages |journal=Am. J. Respir. Crit. Care Med. |volume=159 |issue=2 |pages=508–11 |date=February 1999 |pmid=9927365 |doi= 10.1164/ajrccm.159.2.9804085}} and leukotriene{{cite journal | vauthors=Peters-Golden M, Canetti C, Mancuso P, Coffey MJ | title=Leukotrienes: underappreciated mediators of innate immune responses | journal=Journal of Immunology | year=2005 | pages=589–94 | volume=174 | issue=2 | pmid=15634873 | doi=10.4049/jimmunol.174.2.589 | doi-access=free }} synthesis, and reduce inflammation and innate immunity and
2. nonselective adenosine receptor antagonists{{cite journal | vauthors =Daly JW, Jacobson KA, Ukena D | title=Adenosine receptors: development of selective agonists and antagonists | journal=Prog Clin Biol Res | year=1987 | pages=41–63 | volume=230 | issue=1 | pmid=3588607 }}

But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthine derivatives (some nonmethylated) have been developed in the search for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes.{{cite journal | last1 = MacCorquodale | first1 = DW | title = The Synthesis of Some Alkylxanthines1,2 | date = July 1929 | journal = Journal of the American Chemical Society | volume = 51 | issue = 7| pages = 2245–2251 | doi = 10.1021/ja01382a042 }}[http://www.wipo.int/pctdb/en/wo.jsp?amp%3BIA=WO1985%2F02540&%3BDISPLAY=DESC&IA=US1984002035&WO=1985%2F02540&DISPLAY=CLAIMS WO patent 1985002540] {{Webarchive|url=https://web.archive.org/web/20110805103634/http://www.wipo.int/pctdb/en/wo.jsp?amp%3BIA=WO1985%2F02540&%3BDISPLAY=DESC&IA=US1984002035&WO=1985%2F02540&DISPLAY=CLAIMS |date=2011-08-05 }}, Sunshine A, Laska EM, Siegel CE, "ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING XANTHINES AND METHODS OF USING SAME", granted 1989-03-22, assigned to RICHARDSON-VICKS, INC.{{Ref patent3 | country = US | number = 4288433 | status = granted | title = Cosmetic compositions having a slimming action | pubdate = 1979-09-24 | gdate = 1981-09-04 | pridate= 1979-09-24 | inventor = Constantin Koulbanis, Claude Bouillon, Patrick Darmenton | assign1= L'Oreal | google_patent_id = 96M6AAAAEBAJ }}{{cite journal | vauthors = Daly JW, Padgett WL, Shamim MT | title = Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors | journal = Journal of Medicinal Chemistry | volume = 29 | issue = 7 | pages = 1305–8 |date=July 1986 | pmid = 3806581 | doi = 10.1021/jm00157a035}}{{cite journal | vauthors = Daly JW, Jacobson KA, Ukena D | title = Adenosine receptors: development of selective agonists and antagonists | journal = Progress in Clinical and Biological Research | volume = 230 | pages = 41–63 | year = 1987 | pmid = 3588607 }}{{cite journal | vauthors = Choi OH, Shamim MT, Padgett WL, Daly JW | title = Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors | journal = Life Sciences | volume = 43 | issue = 5 | pages = 387–98 | year = 1988 | pmid = 2456442 | doi = 10.1016/0024-3205(88)90517-6| url =https://zenodo.org/record/1253962 }}{{cite journal | vauthors = Shamim MT, Ukena D, Padgett WL, Daly JW | title = Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions | journal = Journal of Medicinal Chemistry | volume = 32 | issue = 6 | pages = 1231–7 |date=June 1989 | pmid = 2724296 | doi = 10.1021/jm00126a014}}{{cite journal | vauthors = Daly JW, Hide I, Müller CE, Shamim M | title = Caffeine analogs: structure-activity relationships at adenosine receptors | journal = Pharmacology | volume = 42 | issue = 6 | pages = 309–21 | year = 1991 | pmid = 1658821 | doi = 10.1159/000138813| url = https://zenodo.org/record/1235428}}{{cite journal | vauthors = Ukena D, Schudt C, Sybrecht GW | title = Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes | journal = Biochemical Pharmacology | volume = 45 | issue = 4 | pages = 847–51 |date=February 1993 | pmid = 7680859 | doi = 10.1016/0006-2952(93)90168-V}}{{cite journal | author = Daly JW | title = Alkylxanthines as research tools | journal = Journal of the Autonomic Nervous System | volume = 81 | issue = 1–3 | pages = 44–52 | date = July 2000 | pmid = 10869699 | doi = 10.1016/S0165-1838(00)00110-7 | url = https://zenodo.org/record/1259863 }}{{cite journal | author = Daly JW | title = Caffeine analogs: biomedical impact | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 16 | pages = 2153–69 |date=August 2007 | pmid = 17514358 | doi = 10.1007/s00018-007-7051-9 | s2cid = 9866539 | url = https://zenodo.org/record/1232583| pmc = 11138448 }}{{cite journal | vauthors = González MP, Terán C, Teijeira M | title = Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we? | journal = Medicinal Research Reviews | volume = 28 | issue = 3 | pages = 329–71 |date=May 2008 | pmid = 17668454 | doi = 10.1002/med.20108 | s2cid = 23923058 }}{{cite journal | vauthors = Baraldi PG, Tabrizi MA, Gessi S, Borea PA | title = Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility | journal = Chemical Reviews | volume = 108 | issue = 1 | pages = 238–63 |date=January 2008 | pmid = 18181659 | doi = 10.1021/cr0682195 }}

• EHNA (erythro-9-(2-hydroxy-3-n{{Not a typo|onyl}})adenine)
• BAY 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one)
• Oxindole
• PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one)

{{Main|PDE3 inhibitor}}

• Amrinone, milrinone and enoximone are used clinically for short-term treatment of cardiac failure. These drugs mimic sympathetic stimulation and increase cardiac output.
• Anagrelide{{cite journal | pmc = 2983030 | pmid=21120194 | doi=10.5045/kjh.2010.45.2.136 | volume=45 | issue=2 | title=Development of acute myocardial infarction in a young female patient with essential thrombocythemia treated with anagrelide: a case report | year=2010 | journal=Korean J Hematol | pages=136–8 |vauthors=Lim YH, Lee YY, Kim JH, Shin J, Lee JU, Kim KS, Kim SK, Kim JH, Lim HK }}
• Cilostazol is used in the treatment of intermittent claudication.
• Pimobendan is FDA approved for veterinary use in the treatment of heart failure in animals.

PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.

File:PDE4-inhibiting thalidomide analogs.svg

{{main|PDE4 inhibitor}}

• Mesembrenone, an alkaloid from the herb Sceletium tortuosum
• Rolipram, used as investigative tool in pharmacological research
• 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.
• Piclamilast, a more potent inhibitor than rolipram.{{cite journal | vauthors =de Visser YP, Walther FJ, Laghmani EH, van Wijngaarden S, Nieuwland K, Wagenaar GT | title=Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury | journal=Eur Respir J | year=2008 | pages=633–644 | volume=31 | issue=3 | pmid=18094015 | doi=10.1183/09031936.00071307 | doi-access=free }}
• Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.{{cite journal | vauthors =Yu MC, Chen JH, Lai CY, Han CY, Ko WC | title=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 | journal=Eur J Pharmacol | year=2009 | pages=269–75 | volume=627 | issue=1–3 | pmid=19853596 | doi=10.1016/j.ejphar.2009.10.031 }}
• Drotaverine, used to alleviate renal colic pain, also to hasten cervical dilatation in labor
• Roflumilast, indicated for people with severe COPD to prevent symptoms such as coughing and excess mucus from worsening{{cite web|url=http://pharmacistsociety.skipta.com/article.aspx/o/4c18ca7f-1da9-4587-b304-64014e651663/09b6025d-60a0-4657-8b3f-b78ffc8f6f1c|title=Powered by Skipta technology, PharmacistSociety.com is the social network for verified Pharmacists to communicate and collaborate.|website=pharmacistsociety.skipta.com|access-date=1 May 2018|url-status=dead|archive-url=https://web.archive.org/web/20120419174156/http://pharmacistsociety.skipta.com/article.aspx/o/4c18ca7f-1da9-4587-b304-64014e651663/09b6025d-60a0-4657-8b3f-b78ffc8f6f1c|archive-date=19 April 2012}}
• Apremilast, used to treat psoriasis and psoriatic arthritis.
• Crisaborole, used to treat atopic dermatitis.
• 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.

PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD, and rhinitis. They suppress the release of cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects{{cite journal | vauthors =Bobon D, Breulet M, Gerard-Vandenhove MA, Guiot-Goffioul F, Plomteux G, Sastre-y-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H | title=Is phosphodiesterase inhibition a new mechanism of antidepressant action? A double blind double-dummy study between rolipram and desipramine in hospitalized major and/or endogenous depressives | journal=Eur Arch Psychiatry Neurol Sci | year=1988 | pages=2–6 | volume=238 | issue=1 | pmid=3063534 | doi=10.1007/BF00381071 | s2cid=7795640 }} and have also been proposed for use as antipsychotics.{{cite journal | vauthors =Maxwell CR, Kanes SJ, Abel T, Siegel SJ | title=Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications | journal=Neuroscience | year=2004 | pages=101–7 | volume=129 | issue=1 | pmid=15489033 | doi = 10.1016/j.neuroscience.2004.07.038 | s2cid=19578277 }}{{cite journal | vauthors =Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP | title=Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity | journal=Neuroscience | year=2006 | pages=239–46 | volume=144 | issue=1 | pmid=17081698 | doi=10.1016/j.neuroscience.2006.09.026 | pmc=3313447}}

On October 26, 2009, the University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to hippocampus-based memory functions.{{cite journal | vauthors =Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, Kim SS, Chen T, Shang YZ, Zhuo M, Houslay MD, Abel T | title=Sleep deprivation impairs cAMP signaling in the hippocampus | journal=Nature | year=2009 | pages=1122–1125 | volume=461 | issue=7267 | pmid=19847264 | doi=10.1038/nature08488 | pmc=2783639 | bibcode=2009Natur.461.1122V }}

{{Main|PDE5 inhibitor}}

• Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.
• Dipyridamole also inhibits PDE5. This results in added benefit when given together with nitric oxide or statins.

Recent studies have shown quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents.{{Cite journal | last1 = Redondo | first1 = M. | last2 = Zarruk | first2 = JG. | last3 = Ceballos | first3 = P. | last4 = Pérez | first4 = DI. | last5 = Pérez | first5 = C. | last6 = Perez-Castillo | first6 = A. | last7 = Moro | first7 = MA. | last8 = Brea | first8 = J. | last9 = Val | first9 = C. | last10 = Cadavid | first10 = María I. | last11 = Loza | first11 = María I. | last12 = Campillo | first12 = Nuria E. | last13 = Martínez | first13 = Ana | last14 = Gil | first14 = Carmen | title = Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model | journal = Eur J Med Chem | volume = 47 | issue = 1 | pages = 175–85 |date=Jan 2012 | doi = 10.1016/j.ejmech.2011.10.040 | pmid = 22100138 | display-authors = 8 }}

Paraxanthine, the main metabolite of caffeine (84% in humans),{{cite journal|last1=Guerreiro|first1=Serge|last2=Toulorge|first2=Damien|last3=Hirsch|first3=Etienne|last4=Marien|first4=Marc|last5=Sokoloff|first5=Pierre|last6=Michel|first6=Patrick P.|date=October 2008|title=Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels|journal=Molecular Pharmacology|volume=74|issue=4|pages=980–989|doi=10.1124/mol.108.048207|issn=1521-0111|pmid=18621927|s2cid=14842240}} is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase.{{Cite web|url=https://www.caymanchem.com/pdfs/21068.pdf|title=Paraxanthine}}{{Cite journal|last1=Orrú|first1=Marco|last2=Guitart|first2=Xavier|last3=Karcz-Kubicha|first3=Marzena|last4=Solinas|first4=Marcello|last5=Justinova|first5=Zuzana|last6=Barodia|first6=Sandeep Kumar|last7=Zanoveli|first7=Janaina|last8=Cortes|first8=Antoni|last9=Lluis|first9=Carme|last10=Casado|first10=Vicent|last11=Moeller|first11=F. Gerard|date=April 2013|title=Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans|journal=Neuropharmacology|volume=67C|pages=476–484|doi=10.1016/j.neuropharm.2012.11.029|issn=0028-3908|pmc=3562388|pmid=23261866}} PDE9 is expressed as high as PDE5 in the corpus cavernosum.{{Cite journal|last1=da Silva|first1=F H|last2=Pereira|first2=M N|last3=Franco-Penteado|first3=C F|last4=De Nucci|first4=G|last5=Antunes|first5=E|last6=Claudino|first6=M A|date=March 2013|title=Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide–cyclic GMP pathway in mice|journal=International Journal of Impotence Research|volume=25|issue=2|pages=69–73|doi=10.1038/ijir.2012.35|pmid=23034509|issn=0955-9930|doi-access=free}}

Papaverine, an opium alkaloid, has been reported to act as a PDE10 inhibitor.{{cite journal | pmc = 2748940 | pmid=19066855 | doi=10.1007/s00213-008-1419-x | volume=203 | issue=4 | title=Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine | date=May 2009 | journal=Psychopharmacology | pages=723–35 |vauthors=Weber M, Breier M, Ko D, Thangaraj N, Marzan DE, Swerdlow NR }}Inhibitory Mechanism of Papaverine on Carbachol-Induced Contraction in Bovine Trachea; Takeharu Kaneda1,*, Yukako Takeuchi1, Hirozumi Matsui1, Kazumasa Shimizu1, Norimoto Urakawa1,and Shinjiro Nakajyo, Division of Veterinary Pharmacology, Nippon Veterinary and Animal Science University; http://www.jstage.jst.go.jp/article/jphs/98/3/275/_pdf{{Dead link|date=May 2020 |bot=InternetArchiveBot |fix-attempted=yes }}{{cite journal | doi=10.1016/0024-3205(71)90086-5 | pmid=4325052 | volume=10 | issue=3 | title=Papaverine - induced inhibition of phosphodiesterase activity in various mammalian tissues | journal=Life Sciences | pages=133–144| year=1971 | last1=Pöch | first1=G. | last2=Kukovetz | first2=W.R. }}

PDE10A is almost exclusively expressed in the striatum and subsequent increase in cAMP and cGMP after PDE10A inhibition (e.g. by papaverine) is "a novel therapeutic avenue in the discovery of antipsychotics".Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats; An Torremans, Abdellah Ahnaou, An Van Hemelrijck, Roel Straetemans, Helena Geys, Greet Vanhoof, Theo F. Meert, and Wilhelmus H. Drinkenburg; {{cite web |url=http://www.ane.pl/pdf/7002.pdf |title=Archived copy |access-date=2011-08-27 |url-status=live |archive-url=https://web.archive.org/web/20111007095852/http://www.ane.pl/pdf/7002.pdf |archive-date=2011-10-07 }}

{{Reflist}}

{{Phosphodiesterase inhibitors}}

{{Enzyme inhibition}}

{{Authority control}}

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