Download Women alike can suffer the same condition as men resulting in an

Sildenafil (Viagra)
University of California of San Diego
Author’s Note
This group final paper was written for Dr. James Whitesell’s Chemistry 151: Molecules
that Changed the World, Winter 2013.
Abstract/Introduction
It was 1995 and Charles Hancock, 65 years old with diabetes, had recently begun
experiencing difficulties in the bedroom. That is, he could not get it up. He explained to his wife
and the doctor that he was still very sexually aroused by Mary, the love of his life for 30 years,
but could not seem to get his penis erect as he used to when he was in his prime. One year later,
Charles’s sex life, unbeknownst to him, would be saved due to a miracle drug called Viagra.
Charles Hancock continued his marriage no longer sexually frustrated but happy, satisfied, and
with an orange prescription bottle for Viagra next to his bed.
Figure 1. A comic depicting the common use of Viagra to induce erections
Sildenafil Citrate, popularly known by its trade names Viagra and Revatio, was synthesized
at Pfizer in England. Initially, Sildenafil was studied for its effects in hypertension (high blood
pressure) and angina pectoris (chest pain due to ischemic heart disease). During the phase 1
clinical trials, it was observed that Sildenafil did not have any significant effects on angina;
however, it was noted that it induced penile erections. This breakthrough for erectile dysfunction
led to Pzifer’s patent and approval of the drug in the United States in 1996.
In recent statistics, approximately 30 million males in the United States of America are
battling different severities of erectile dysfunction. Women alike can suffer the same condition as
men resulting in an insufficient blood flow to the clitoris. But treated with Sildenafil, women too
could rectify the dysfunction. Many origins of erectile dysfunction are actually caused by
diabetes, drug use, vascular disease, hormone disorders, neurologic disorders, pelvic trauma,
radiation exposure, venous sleep, psychological problems and /or Pyrenees disease and not just
impotence. With minimal side effects such as flushing, congestion, headache, blurred vision,
priapism of up to seven hours, Viagra is available through prescription but is only effective with
sexual arousal and does not increase sexual drive or libido as some may think. It is now known
as a drug used to treat various conditions including pulmonary arterial hypertension, high blood
pressure, high-altitude pulmonary edema known as altitude sickness, jet lag and vasculogenic
impotence. Thus, a multi-billion dollar market worldwide of Viagra emerged.
Commercial Synthesis of Sildenafil
The preparation steps for synthesis of sildenafil are as follows:
1. Methylation of 3propylpyrazole-5-carboxylic
acid ethyl ester with hot
dimethyl sulfate.
Hydrolysis with aqueous
NaOH to free acid
2. Nitration with oleum/fuming
nitric acid
3. Carboxamide formation with
refluxing thionyl
chloride/NH4OH
4. Reduction of nitro group to
amino
5. Acylation with 2ethoxybenzoyl chloride
6. Cyclization
7. Sulfonation to the
chlorosulfonyl derivative
8. Condensation with 1methylpiperazine.
Figure 2: Commercial Synthesis of Sildenafil
Biological Mechanism
On a normal physiological scale, an erection would begin with sexual stimulation that would
trigger a release of neurotransmitters from the cavernous nerve in the endothelial cell. Here is a
more detailed account of what occurs in the endothelial cell:
1. Dilatation of the arterioles and arteries by increased blood flow in both the diastolic and
the systolic phases
2. Trapping of the incoming blood by the expanding sinusoids
3. Compression of the subtunical venular plexuses between the tunica albuginea and the
peripheral sinusoids, reducing the venous outflow
4. Stretching of the tunica to its capacity, which occludes the emissary veins between the
inner circular and the outer longitudinal layers and further decreases the venous outflow
to a minimum
5. An increase in PO2 (to about 90 mmHg) and intracavernous pressure (around 100 mm
Hg), which raises the penis from the dependent position to the erect state (the fullerection phase)
6. A further pressure increase (to several hundred millimeters of mercury) with contraction
of the ischiocavernosus muscles (rigid-erection phase)
Figure 3. Release of neutransmitters from the caverous nerve in the endothelial cell.
This process allows relaxation of smooth muscles from the release of nitric oxide. The nitric
oxide is released in the smooth muscles causing a dilation of arteries to increase the blood flow
through the penile walls.
“Smooth muscle contraction and relaxation are regulated by cytosolic (sarcoplasmic) free
Calcium, Ca2+. Norepinephrine from nerve endings and endothelins and prostaglandin F2α from
endothelium activate receptors on smooth muscle cells to increase inositol triphosphate and
diacylglycerol. This results in release of calcium from intracellular stores such as sarcoplasmic
reticulum and/or opening of calcium channels on the smooth muscle cell membrane leading to an
influx of calcium from extracellular space. This triggers a transient increase in cytosolic free
Ca2+ from a resting level of 120 to 270 to 500 to 700 nM.
At the elevated level, Ca2+ binds to calmodulin and
changes the latter’s conformation to expose sites of
interaction with myosin light-chain kinase. The resultant
activation catalyzes phosphorylation of myosin light
chains and triggers cycling of myosin crossbridges
(heads) along actin filaments and the development of
force. In addition, phosphorylation of the light chain also
activates myosin ATPase, which hydrolyzes ATP to
provide energy for muscle contraction” (Dean). In other
words, free Ca2+ continues the erection state until natural dissipation through an enzymatic
breakdown by phosphodiesterase type 5 from cGMP into GMP. Viagra acts on this mechanism
by blocking the phosphodiesterase type 5 allowing the free Ca2+ to continue the muscles
relaxation for longer until the Sildenafil decays.
References
Dean, Richard. "Physiology of Penile Erection and Pathophysiology of Erectile
Dysfunction." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351051/#R32. Urologic Clinics of
North America, 25 Jan. 2006. Web. 7 Feb. 2014.
Dunn, Peter J. "Synthesis of Commercial Phosphodiesterase(V) Inhibitors." Organic Process
Research & Development 9.1 (2005): 88-97.