Download PDE5 selective inhibitors

Phosphodiesterases
A phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond.
Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide
phosphodiesterases, which have great clinical significance and are described below.
However, there are many other families of phosphodiesterases, including
phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases,
RNases, and restriction endonucleases (which all break the phosphodiester backbone
of DNA or RNA), as well as numerous less-well-characterized small-molecule
phosphodiesterases.
The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade
the phosphodiester bond in the second messenger molecules cAMP and cGMP. They
regulate the localization, duration, and (cellular level)amplitude of cyclic nucleotide
signaling within subcellular domains. PDEs are therefore important regulators of
signal transduction mediated by these second messenger molecules.
There are 11 subtypes of PDEs, named PDE1-11; PDE4, 7 and 8 selectively degrade cAMP,
PDE5, 6 and 9 selectively degrade cGMP and PDE1, 2, 3, 10 and 11 degrade both cyclic
nucleotides( with over 50 isotypes). PDEs are expressed ubiquitously, with each subtype
having a specific tissue distribution. These enzymes are involved in many signal transduction
pathways and their functions include vascular smooth muscle proliferation and contraction,
cardiac contractility, platelet aggregation, hormone secretion, immune cell activation, and
they are involved in learning and memory.
PDE
1
2
3
4
5
6
7
8
9
10
11
Main tissue localization
Brain , Haert,Vascular smooth muscle.
Adrenal cortex, Brain, Haert , Corpus covernosum.
Haert , Corpus covernosum, Vascular smooth muscle, platelets,
liver, pancreas.
Lung, Mast cell, Vascular smooth muscle.
Haert, Corpus covernosum, Vascular smooth muscle,
platelets,Brain, esophagus.
Retina.
Skeletal Muscle, T cell.
Testis, Thyroid.
Broadly expressed, not well characterized.
Brain , Testes.
Skeletal Muscle, Prostate,Liver, Kidny, Pitutary,Testis
Phosphodiesterase inhibitor
A phosphodiesterase inhibitor is a drug that blocks one or more of the subtypes of
the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the
intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP) by the respective PDE subtype(s).
Classification
They are classified into selective and nonselective phosphodiesterase
inhibitors
Nonselective phosphodiesterase inhibitors
Methylated xanthines and derivatives:
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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
theobromine
theophylline, a bronchodilator
Methylated xanthines act as both
competitive nonselective phosphodiesterase inhibitors, which raise intracellular
cAMP, activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce
inflammation and innate immunity and nonselective adenosine receptor
antagonists
selective phosphodiesterase inhibitors
PDE1 selective inhibitors
 Vinpocetine
PDE2 selective inhibitors
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BAY 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one)
Oxindole
EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)
PDE3 selective inhibitors
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Milrinone and Enoximone are used clinically for short-term treatment of
cardiac failure.
These drugs mimic sympathetic stimulation and increase cardiac output.
Anagrelide
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.
PDE4 selective inhibitors
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Mesembrine, Rolipram,
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,Luteolin,
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[
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 and have
also recently been proposed for use as antipsychotics.[28][29]
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 Hippocampusbased memory functions
PDE5 selective inhibitors
PDE5 has only one subtype, PDE5A, of which there are 4 isoforms in humans called
PDE5A1-4.
PDE5 enzyme is specific for cGMP which means it only hydrolyzes cGMP but not
cAMP, the selectivity is mediated through network of hydrogen bonding which is
favorable for cGMP but unfavorable for cAMP in PDE5.
PDE5 is responsible for the degradation of cGMP in the smooth muscle cells lining
the blood vessels supplying the corpus cavernosum of the penis, which leads to
erectile dysfunction (ED).
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Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively
inhibit PDE5, in the corpus cavernosum. are used primarily 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 NO or statins.
Claimed newer and more-selective inhibitors are icariin.
PDE7 selective inhibitors
Recently, quinazoline type PDE7 inhibitor to be potent anti-inflammatory and
neuroprotective agents
PDE10 selective inhibitors
Papaverine, an opium alkaloid, PDE10 inhibitor, in the striatum and subsequent
increase in cAMP and cGMP. Papaverine) is "a novel therapeutic in the discovery of
antipsychotics".
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