A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of

phosphodiesterase 4 At least four types of the enzyme phosphodiesterase 4 (PDE4) are known: * PDE4A * PDE4B * PDE4C * PDE4D See also * 3',5'-cyclic-AMP phosphodiesterase * Phosphodiesterase (PDE) * PDE4 inhibitor A phosphodiesterase-4 inhibitor, commonly referred ...

(PDE4) on

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). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

Therapeutic utility

The prototypical PDE4 inhibitor is

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 ...

. PDE4 inhibitors are known to possess procognitive (including

long term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long-t ...

-improving), wakefulness-promoting, neuroprotective, and anti-inflammatory effects. 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 Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...

(clinical depression), anxiety disorders,

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

attention deficit-hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

and inflammatory conditions such as

chronic obstructive pulmonary disease 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 ...

(COPD),

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 ...

and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

. PDE4D inhibition, along with

PDE4A cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the ''PDE4A'' gene. Function The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This P ...

inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors. Similarly

PDE4B cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the ''PDE4B'' gene. This gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. Cyclic nucleotides ar ...

inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors, in line with this view PDE4B polymorphisms and altered gene expression in the central nervous system have been associated with schizophrenia and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

in a postmortem study. PDE4 also regulates the D₁/ PKA/

DARPP-32 Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the ''PPP1R1B'' gene. Function Midbrain dopaminergic neurons play a ...

signalling cascade in the

frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betwe ...

, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors. Whereas

PDE4C cAMP-specific 3',5'-cyclic phosphodiesterase 4C is an enzyme that in humans is encoded by the ''PDE4C'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...

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). PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats, hence suggesting its possible utility in the treatment of

alcohol dependence Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol). In 2013, it was reclassified as alcohol use disorde ...

. 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. A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours. The clinical development of PDE4 inhibitors has been hampered by their potent

emetic Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

effects, which appear to be related to their inhibition of

PDE4D cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the ''PDE4D'' gene. Function The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the s ...

which is expressed in the

area postrema The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and ...

Adverse reactions

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

, and related general gastrointestinal

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s 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 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 ...

Examples

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 ...

, a

phthalimide Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a Sublimation (phase transition), sublimable white solid that is slightly soluble in water but more so upon addition of ba ...

derivative that was approved by the U.S. FDA in March 2014 for use as a treatment for

psoriatic arthritis Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Thi ...

, and in September 2014 for the treatment of

plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

under the brand name Otezla. *

Cilomilast Cilomilast (INN, codenamed SB-207,499, proposed trade name Ariflo) is a drug which was developed for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). It is orally active and acts as a selectiv ...

, in clinical development by

GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...

for treatment of COPD. *

Crisaborole Crisaborole, sold under the brand name Eucrisa among others, is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema) in adults and children. The most common side effects are reactions at the ...

(AN2728), a

boron Boron is a chemical element with the symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the ''boron group'' it has th ...

-containing drug for the topical treatment of

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

and

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in puritis, itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens o ...

.Anaco
AN2728 at Anacor website
Page accessed May 15, 2015 It was approved by the FDA on December 14, 2016 under the brand name Eucrisa for the treatment of mild-to-moderate

(eczema) in patients 2 years of age and older. *

Diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...

, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant. *

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. *

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 fir ...

, supplement extracted from peanuts and other plants 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. *

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 ...

'' (Kanna). *

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. *

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 ...

, 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 and Daliresp. *

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.

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.

References

{{DEFAULTSORT:Pde4 Inhibitor