Sildenafil (Viagra) was developed more than 10 years
ago as an antihypertensive and antianginal drug. It
proved ineffective in these applications but was shown
to affect the smooth muscles of the penis.
Sildenafil (Viagra) is a selective
inhibitor of PD-5, an enzyme that inactivates cGMP.
Vardenifil (Levitra) is a particularly effective inhibitor
of PD-5. It has a shorter onset of action and can be used
in smaller doses than sildenafil. Other drugs used in the
treatment of ED exert their effects through other biochemical
pathways, both central and peripheral.
Indications and Usage
Sildenafil Citrate is an oral drug used to treat male erectile dysfunction and is a 5-phosphodiesterase inhibitor developed by the American Pfizer Pharmaceuticals to originally treat cardiovascular disease that was later discovered to improve patients’ sex lives. Sildenafil Citrate treats erectile dysfunction and was the first clinical oral drug used to specifically target male erectile dysfunction.
An orally active selective type 5 cGMP phosphodiesterase inhibitor.
Sildenafil is a selective inhibitor of cGMP-specific
PD-5 and therefore inhibits the degradation of cGMP.
PD-5, the predominant type in the corpus cavernosum,
also is present in other tissues (e.g., lungs, platelets, and
eye). The selective inhibition of this enzyme facilitates
the release of nitric oxide and smooth muscle relaxation
of the corpus cavernosa. Sildenafil enhances erection by
augmenting nitric oxide–mediated relaxation pathways.
It has been suggested that sildenafil’s mechanism of
action is due to cross-talk between cGMP- and cAMPdependent
transduction pathways within the cavernous
Sildenafil, the first US FDA-approved, oral phosphodiesterase type-5 inhibitor, has revolutionized the treatment of erectile dysfunction sine its approval in 1998. Since sildenafil is a potent inhibitor of cyclic guanosine monophosphate in the corpus cavernosum and therefore increases the penile response to sexual stimulation.
In vitro metabolism studies for sildenafil have shown that the primary metabolite, N-desmethylsildenafil, and the minor metabolite, oxidative opening of the piperazine ring, are mediated by CYP3A4, CYP2C9, CYP2C19, and CYP2D6. The estimated relative contributions to clearance were 79% for CYP3A4, 20% for CYP2C9, and less than 2% for CYP2C19 and CYP2D6. These results demonstrate that CYP3A4 is the primary cytochrome mediating N-demethylation and that drugs inhibiting CYP3A4 likely impair sildenafil biotransformation and clearance. The pharmacokinetics of radiolabeled sildenafil were consistent with rapid absorption, first-pass metabolism, and primarily fecal elimination of N-demethylated metabolites. The absorption of sildenafil following oral administration was rapid (~92%), whereas the oral bioavailability was approximately 38% as a result of first-pass metabolism.
Orally administered sildenafil is an effective and
well-tolerated treatment for men with ED, including
those with diabetes mellitus. It has also been used for
so-called salvage therapy in men who do not respond to
intracorporeal injections of other agents.
Headache is a common side effect, as are flushing
and rhinitis.More serious side effects include definite or
suspected myocardial infarctions and cardiac arrest.
Sildenafil was launched as Viagra in the US for the treatment of organic
orland psychological male erectile dysfunction (ED). Sildenafil can be obtained
by functional rearrangement of the corresponding 5-aryl 1,3-dialkyl pyrazolo[4,3-
d]pyrimidin-7-one, itself synthesized in a seven-step sequence from a pyrazole-
5-carboxylate. Sildenafil is a potent and selective inhibitor of type V cGMP
phosphodiesterases (PDE5) ; IC50 = 3nM on isozymes from human corpus
cavernosum tissue. This orally-active therapy is completely new and presents
advantages over the classically recommended options such as vacuum
constriction devices, drug injection or prosthesis implantation ; for these
reasons, this first drug is likely to have a large acceptance fot the treatment of
male ED. In experiments with incubated rabbit penile tissue, Sildenafil was
shown to cause accumulation of cGMP. By inhibiting the enzyme PDE5, the
predominant isozyme in the corpus cavernosum, Sildenafil induces an elevation
of levels of second messager cGMP, which is involved in the regulation of
vascular tone ; it was suggested that the specific elevation of cGMP due to
Sildefanil would mediate an enhancement of nitric oxide-dependent relaxation of
corpus cavernosal tissue. Several clinical studies using 10-100 mg Sildenafil
have confirmed a good effectiveness and tolerability in healthy males. New trials
in women with sexual disfunction have been initiated and positive results could
enlarge the potential market of this drug.
ChEBI: A pyrazolo[4,3-d]pyrimidin-7-one having a methyl substituent at the 1-position, a propyl substituent at the 3-position and a 2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl group at the 5-position.
Mechanism of action
Sildenafil is readily absorbed after oral administration
and reaches peak plasma levels after about an
hour. It undergoes hepatic metabolism and has a terminal
half-life of about 4 hours.An initial dose of 50 mg is
taken about an hour prior to sexual activity to induce
Common adverse reactions include headache, dizziness, facial flushing, indigestion, nasal congestion, and sight abnormalities, which may be expressed as difficulty differentiation blue/green colors, light sensitivity, or blurry vision. More severe adverse effects include decreased supine blood pressure and decreased cardiac output. Additionally, clinical research shows that engaging in sexual activity after taking Sildenafil Citrate increases the risk of heart abnormalities, including angina pectoris, dizziness, nausea, and other symptoms, and it may also cause sudden cardiac death.
A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 0.132
mol) (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568) and
dimethyl sulfate (16.8 g, 0.133 mol) were heated to 90°C for 2.5 h. The
mixture was dissolved in dichloromethane and the solution washed with
sodium carbonate solution. The organic phase was separated, dried (MgSO4)
and evaporated under vacuum to give a solid. Chromatography on silica gel
(300 g), eluting with dichloromethane gave the 1-methyl-3-n-propylpyrazole-
5-carboxylic acid ethyl ester as a colourless oil (20.4 g, 79%).1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol)
was suspended in 6 N aqueous sodium hydroxide solution (50 ml, 0.30 mol).
The mixture was heated to 80°C for 2 h then diluted with water (50 ml) and
acidified with concentrated hydrochloric acid (25 ml). Filtration gave the 1-
methyl-3-n-propylpyrazole-5-carboxylic acid as pale brown crystals (12.3 g,
71%), melting point 150°-154°C.1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added
portionwise to a mixture of oleum (13 ml) and fuming nitric acid (11 ml),
keeping the temperature below 60°C. After the addition, the mixture was
heated at 60°C overnight and then cooled to room temperature before being
poured onto ice. Filtration of the precipitate gave the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxylic acid as a white solid (11.5 g, 75%), melting point
124°-127°C.1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) was
added to thionyl chloride (50 ml) and the resulting mixture heated under
reflux for 3 h. The reaction mixture was then cooled and excess thionyl
chloride removed by evaporation under vacuum. The oily residue was
dissolved in acetone (50 ml) and the solution cautiously added to a mixture of
ice (50 g) and concentrated aqueous ammonium hydroxide solution (50 ml).
The precipitate was collected by filtration to provide the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxamide as a pale yellow solid (8.77 g, 78%), melting
point 141°-143°C.1-Methyl-4-nito-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and
stannous chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol and
the mixture heated under reflux for 2 h. The resulting solution was cooled to
room temperature, basified to pH 9 by the addition of 2 N aqueous sodium
hydroxide solution and extracted with dichloromethane (3 x 150 ml). The
organic extracts were combined, dried (MgSO4) and evaporated under
vacuum. Trituration of the residue with ether gave the 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide as an off-white solid (2.77 g, 94%), melting
point 98°-101°C.A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane
(50 ml) was added to a stirred solution of 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine
(0.02 g, 0.1 64 mmol) and triethylamine (3.34 g, 33.0 mmol) in
dichloromethane (50 ml) at 0°C. The resulting mixture was allowed to warm
to room temperature and stirred for a further 2 h. The solvent was evaporated
under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane
and methanol (250 ml), and then the solution washed with 1 N hydrochloric
acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude
material was chromatographed on silica gel (200 g), eluting with a 97:3
mixture of dichloromethane and methanol, to give a pink solid; crystallisation
from ethyl acetate-hexane gave the 4-(2-ethoxybenzamido)-1-methyl-3-npropylpyrazole-
5-carboxamide as a pale pink solid (2.2 g, 40%), melting point
153°-155°C.4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g,
0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g,
1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml).
Ethanol (700 ml) was added and the resulting mixture heated under reflux for
2.5 h, cooled, then evaporated under vacuum. The resulting solid was treated
with 2 N hydrochloric acid (380 ml), with external cooling, and the mixture
was extracted with dichloromethane (1 x 700 ml, 3 x 200 ml). The combined
organic extracts were washed successively with saturated aqueous sodium
carbonate solution (3 x 400 ml) and brine (300 ml), then dried (Na2SO4) and
evaporated under vacuum. Chromatography of the residue on silica gel (1000
g), using a methanol in dichloromethane elution gradient (0-1%), followed by
trituration of the crude product with ether (300 ml), gave the 5-(2-
7-one as a colourless solid (152.2 g, 72%), melting point 143°-146°C.5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to
chlorosulfonic acid (20 ml) at 0°C under a nitrogen atmosphere. After being
stirred overnight, the reaction solution was cautiously added to ice-water (150ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane
and methanol (4 x 100 ml). The combined extracts were dried (Na2SO4) and
evaporated under vacuum to give the required 5-(5-chlorosulphonyl-2-
7-one as a white solid (12.8 g, 97%), melting point 179°-181°C.4-Methylpiperidine was added to a stirred suspension of 5-(5-chlorosulphonyl-
d]pyrimidin-7-one in ethanol at room temperature. The resulting mixture was
stirred for 4 days before removing the solvent by evaporation under vacuum.
The residue was dissolved in a 9:1 mixture of dichloromethane and methanol
and the solution washed with saturated aqueous sodium carbonate solution.
The aqueous phase was further extracted with dichloromethane-methanol
mixtures (3 x 100 ml) and all the organic fractions were combined, dried
(MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a
mixture of methanol-dimethylformamide gave the 5-[2-ethoxy-5-(4-
4,3-d]-pyrimidin-7-one as an off-white solid, melting point 187°-
189°C.After addition of citric acid to the 5-[2-ethoxy-5-(4-
4,3-d]-pyrimidin-7-one (sildenafil) the it's salt is obtained, namely
Sildenafil is rapidly absorbed and peaks in concentration (127–560 ng/mL) after 0.5 to 2.0 hours, displaying a half-life of 3 to 4 hours
for the full therapeutic dose (25–100 mg). It is 96% bound to plasma proteins and is metabolized by the liver CYP3A4. The
metabolite N-desmethylsildenafil possesses approximately 50% of the activity of the parent molecule.