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A phosphodiesterase inhibitor is a
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
that blocks one or more of the five subtypes of the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...
(PDE), thereby preventing the inactivation of the intracellular
second messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
s,
cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) and
cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in re ...
(cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.


History

The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction meanwhile has proved to be true in a variety of fields.


Classification


Nonselective PDE inhibitors

Methylated
xanthines Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, ...
and derivatives: *
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
, a minor
stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
* aminophylline *
IBMX IBMX (3-isobutyl-1-methylxanthine), like other methylated xanthine, xanthine derivatives, is both a: # competitive non-selective phosphodiesterase inhibitor which raises intracellular Cyclic adenosine monophosphate, cAMP, activates cAMP-dependent ...
(3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research *
paraxanthine Paraxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Production and metabolism Paraxanthine is not known to be produced by plants but is observed in nature as a metabolite of caffeine in a ...
* 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 *
theobromine Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water-soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
*
theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
, a
bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lung ...
Methylated
xanthines Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, ...
act as both # competitive nonselective
phosphodiesterase inhibitors A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cycli ...
, which raise intracellular
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, activate PKA, inhibit TNF-alpha and
leukotriene Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. Leukotrienes ...
synthesis, and reduce inflammation and
innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
and # nonselective
adenosine receptor The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
antagonists 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 The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
subtypes.


PDE2 selective inhibitors

*
EHNA EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine) is a potent adenosine deaminase inhibitor, which also acts as a phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphod ...
(erythro-9-(2-hydroxy-3-n)adenine) *
BAY 60-7550 BAY 60-7550 is a type 2 phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second m ...
(2- 3,4-dimethoxyphenyl)methyl7- 1R)-1-hydroxyethyl4-phenylbutyl]-5-methyl-imidazo ,1-f1,2,4]triazin-4(1H)-one) *
Oxindole Oxindole (2-indolone) is an aromatic heterocyclic organic compound with the formula C6H4CHC(O)NH. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing ring. Oxindole is a modified indo ...
* PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one)


PDE3 selective inhibitors

*
Amrinone Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initia ...
,
milrinone Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistan ...
and
enoximone Enoximone ( INN, trade name Perfan) is an imidazole phosphodiesterase inhibitor. It is used in the treatment of congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and s ...
are used clinically for short-term treatment of
cardiac failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, an ...
. These drugs mimic sympathetic stimulation and increase
cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: t ...
. *
Anagrelide Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia), or overproduction of blood platelets. It also has been u ...
*
Cilostazol Cilostazol, sold under the brand name Pletal among others, is a medication used to help the symptoms of intermittent claudication in peripheral vascular disease. If no improvement is seen after 3 months, stopping the medication is reasonable. It ...
is used in the treatment of
intermittent claudication Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion (ache, cramp, numbness or sense of fatigue), classically in the calf muscle, which occurs during exercise, such as walking, and ...
. *
Pimobendan Pimobendan (INN, or pimobendane; tradenames Vetmedin, Acardi) is a veterinary medication. It is a calcium sensitizer and a selective inhibitor of phosphodiesterase 3 (PDE3) with positive inotropic and vasodilator effects. Pimobendan is used in ...
is FDA approved for veterinary use in the treatment of heart failure in animals.
PDE3 PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of ...
is sometimes referred to as cGMP-inhibited phosphodiesterase.


PDE4 selective inhibitors

*
Mesembrenone Mesembrenone is an alkaloid constituent of ''Sceletium tortuosum'' (Kanna) and minor constituent of Lampranthus aureus and Lampranthus spectabilis Similar to modern synthetic antidepressants, it is a potent (IC50 < 1 μM) selective inhibitor ...
, an alkaloid from the herb ''
Sceletium tortuosum Sceletium tortuosum is a succulent plant commonly found in South Africa, which is also known as Kanna, Channa, Kougoed (Kauwgoed/ 'kougoed', prepared from 'fermenting' ''S. tortuosum'')—which literally means, 'chew(able) things' or 'something ...
'' *
Rolipram Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts ...
, used as investigative tool in pharmacological research *
Ibudilast Ibudilast (development codes: AV-411 or MN-166) is an anti-inflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE4 subtype to the greatest extent, but also showing significant inhibition of other ...
, 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 Piclamilast (RP 73401), is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary ...
, a more potent inhibitor than rolipram. *
Luteolin Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin is the principal yellow dye compound that is obtained from the plant '' Reseda luteola'', which has been used as a source of the dye since at least the f ...
, supplement extracted from peanuts that also possesses
IGF-1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans is ...
properties. * Drotaverine, used to alleviate renal colic pain, also to hasten cervical dilatation in labor *
Roflumilast Roflumilast, sold under the trade name Daxas among others, is a drug that acts as a selective, long-acting inhibitor of the enzyme phosphodiesterase-4 (PDE-4). It has anti-inflammatory effects and is used as an orally administered drug for the ...
, indicated for people with severe COPD to prevent symptoms such as coughing and excess mucus from worsening *
Apremilast Apremilast, sold under the brand name Otezla among others, is a medication for the treatment of certain types of psoriasis and psoriatic arthritis. It may also be useful for other immune system-related inflammatory diseases. The drug acts as a se ...
, used to treat psoriasis and psoriatic arthritis. * Crisaborole, used to treat atopic dermatitis. 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 disease Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bron ...
s such as
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce mu ...
, and
rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip. The inflammation is caused by viruses, bacteria, irritants o ...
. They suppress the release of
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also been proposed for use as
antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...
s. On October 26, 2009,
The University of Pennsylvania The University of Pennsylvania (also known as Penn or UPenn) is a private research university in Philadelphia. It is the fourth-oldest institution of higher education in the United States and is ranked among the highest-regarded universitie ...
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.


PDE5 selective inhibitors

*
Sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...
,
tadalafil Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half ...
,
vardenafil Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the brand name Levitra among others. Medical use Vardenafil's indications and contraindications are the same as with other PDE5 inhibitors; it is closel ...
, and the newer
udenafil The drug udenafil is marketed under the trade name Zydena. It is within the PDE5 inhibitor class (which also includes avanafil, sildenafil, tadalafil, and vardenafil). Like other PDE5 inhibitors, it is used to treat erectile dysfunction. Uden ...
and
avanafil Avanafil is a PDE5 inhibitor approved for erectile dysfunction by the FDA on April 27, 2012 and by EMA on June 21, 2013. Avanafil is sold under the brand names Stendra and Spedra. It was invented at Mitsubishi Tanabe Pharma, formerly known as Ta ...
selectively inhibit
PDE5 Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme () from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to p ...
, 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 Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
, as well as having some other medical applications such as treatment of pulmonary hypertension. *
Dipyridamole Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a s ...
also inhibits PDE5. This results in added benefit when given together with
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
or
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...
s.


PDE7 selective inhibitors

Recent studies have shown
Quinazoline Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid ...
type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents.


PDE9 selective inhibitors

Paraxanthine Paraxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Production and metabolism Paraxanthine is not known to be produced by plants but is observed in nature as a metabolite of caffeine in a ...
, the main metabolite of
Caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
(84% in humans), is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase. PDE9 is expressed as high as PDE5 in the corpus cavernosum.


PDE10 selective inhibitors

Papaverine Papaverine (Latin '' papaver'', "poppy") is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms (especially those involving the intestines, heart, or brain), occasionally in the treatment of e ...
, an
opium Opium (or poppy tears, scientific name: ''Lachryma papaveris'') is dried latex obtained from the seed capsules of the opium poppy ''Papaver somniferum''. Approximately 12 percent of opium is made up of the analgesic alkaloid morphine, which i ...
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
, has been reported to act as a PDE10 inhibitor. PDE10A is almost exclusively expressed in the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
and subsequent increase in cAMP and cGMP after PDE10A inhibition (e.g. by
papaverine Papaverine (Latin '' papaver'', "poppy") is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms (especially those involving the intestines, heart, or brain), occasionally in the treatment of e ...
) 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;


References

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