Download Sildenafil (Viagra) University of California of San Diego By Trang

 Sildenafil (Viagra) University of California of San Diego By Trang Nguyen and Elissa Min 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, Charles Hancock, a 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 the love of his life for 30 years, Mary, but could not seem to produce an erection. Three years later, After Sildenafil became available to the general public, Charles’ sex life, unbeknownst to him, would return to normal. Sildenafil Citrate, popularly known for its trade name
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. It is now recognized as a drug used to treat
various conditions including pulmonary arterial hypertension,
high blood pressure, and high-altitude pulmonary edema
known as altitude sickness, jet lag, vasculogenic impotence
and most importantly sexually dysfunction. Viagra is
available through prescription but is only effective with sexual arousal and does not increase
sexual drive. Some sources of erectile dysfunction caused by diabetes, drug use (antidepressant),
vascular disease, hormone disorders, neurologic disorders, pelvic trauma, radiation exposure,
venous sleep, psychological problems and /or Pyrenees disease and not just impotence. People
who were taking antidepressant would also experience sexual dysfunction may also be benefit by
this drug. This breakthrough for erectile dysfunction led to Pzifer’s patent and approval 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. Some side effects of Sildenafil include
flushing, congestion, headache, blurred vision, priapism of up to seven hours, and in rare cases
some users claimed of loss of vision. Thus, this accidental miracle drug began a multi-billion
dollar market.
Next the Commercial Synthesis of Sildenafil
will be explained.
The preparation steps for synthesis of
sildenafil are as follows:
Peter J. Dunn* Chemical Research and DeVelopment, Pfizer
Global Research and DeVelopment, Sandwich, CT13 9NJ
Kent, UK
The nitro pyrazole 4 can be prepared by
a number of routes (see section 2.4). The
sulphonamide 5 is prepared by
chlorosulphonation chemistry. The two
halves of the molecule, 4 and 5, are put
together by a hydrogenation, activation,
and acylation sequence in which the
three reactions are telescoped into a
single process using ethyl acetate as
solvent. The overall isolated yield of
compound 6 for this three step reaction
sequence is 96%. In the cyclisation
reaction of 6 to give sildenafil, a
potential problem is that the ethoxygroup
is doubly activated to nucleophilic
substitu- tion by the sulphonamide and
amide groups; side reactions can be
reduced by careful choice of reaction
conditions. The isolated yield for this
reaction is 95%, though the reaction
yield is around 99%. Finally the
synthesis is completed by converting the
sildenafil base to the citrate salt in 100%
yield. The very high yields late in the
synthesis and the use of a single solvent
(ethyl acetate) for the three telescoped
steps (allowing easy solvent recovery without the
to fraction- ally separate different solvents) ensure
the environmental profile of the process is very
clean.
need
that
In addition, the synthesis of pyrazole labeled 4 starts from 2-pentanone, and the first
stage is the condensation reaction with the diester of oxalic acid.With the regiochemistry
in the condensation reaction optimised, the next stage is to form the pyrazole. This can be
done by reaction with hydrazine followed by methylation17 or alternatively by reaction
with methylhydrazine (see later). For the alkylation reaction there is a tendency to obtain
the desired N-1 isomer under acidic or neutral conditions17 and the undesired N-2 isomer
under basic conditions. The N-1 isomer, formed under acidic or neutral conditions, can
then be converted into pyrazole 4 by hydrolysis, nitration, and amide formation. The
schematic synthesis of the pyrazole is depicted in the illustration below.
Peter J. Dunn*Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment, Sandwich, CT13
9NJ Kent, UK
Next the biological mechanism will be explained and how Viagra works in vivo. On a normal
physiological scale, an erection would start with sexual stimulation that would trigger a release
of neurotransmitters from the cavernous nerve in the endothelial cell. And this would allow
relaxation of smooth muscles from the release of nitric oxide causing a dilation of arteries to
increase the blood flow through the penile walls. The following are a detailed account for what
was happening 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
Robert C. Dean, Tom F. Lue
occludes the
Urol Clin North Am. Author manuscript; available in PMC 2006 January 25.
Published in final edited form as: Urol Clin North Am. 2005 November; 32(4): 379–
emissary veins
v. doi: 10.1016/j.ucl.2005.08.007
between the inner
PMCID: PMC1351051
circular and the
outer longitudinal
layers and further decreases the venous outflow to a minimum
5. Full-erection phase: 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
6. rigid-erection phase: A further pressure increase (to several hundred millimeters of
mercury) with contraction of the ischiocavernosus muscles
Smooth muscle contraction and relaxation are regulated by cytosolic
(sarcoplasmic) free Ca2+. Norepinephrine from the nerve endings as well as
endothelins and prostaglandin F2α from endothelium activated the receptors on
smooth muscle cells to increase inositol triphosphate and diacylglycerol. As the
result, calcium molecules are released from the intracellular stores such as
sarcoplasmic reticulum and opens 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 the
excited level of 500 to 700 nM.32At the elevated level, Ca2+ binds to calmodulin and
changes the latter’s conformation to expose sites of interaction with myosin lightchain 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, more ATP can be hydrolyzed by
phosphorylation of the light chain which has the ability to activate mysosin ATPase.
Free Ca2+ continues the erection state until
natural dissipation through an enzymatic
breakdown by phosphodiesterase type 5 from
cGMP into GMP. Sildenafil has a structure
resemblance as the cGMP, and the molecules
have the ability to bind to the receptors for
cGMP, which would delay the breakdown of
cGMP, As the result blood flow would
increase to the penis and prolong the erection
stage. Viagra acts on this mechanism by
blocking the phosphodiesterase type 5
allowing the free Ca2+ to continue the muscles
relaxation for longer until the effect of
Sildenafil faded away.
Charles Hancock now sleeps with a
bottle of Viagra on the nightstand and a satisfaction he has not felt for years.
References
Dean, Richard. "Physiology of Penile Erection and Pathophysiology of Erectile
Dysfunction." Http://www.ncbi.nlm.nih.gov/. 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.