Sildenafil

1
Sildenafil The Blue and White Pill By Verity Jane
Litchfield
Revatio Revatio is the same active pharmaceutical
ingredient sildenafil citrate but it is used in
the treatment for the rare disease pulmonary
arterial hypertension (PAH). It works with the
same mechanism as Viagra for relaxing the smooth
muscle. In this case relaxes the arterial wall
leading to decreased pulmonary arterial
resistance and pressure this leads to a reduction
in the workload of the right ventricle and
improves symptoms of right-sided heart failure.
The FDA approved Revatio for use for PAH in 2005.
Synthesis of Sildenafil
Sildenafil citrate more commonly known as Viagra
the erectile dysfunction (ED) treatment but also
marketed as Revatio a treatment for pulmonary
arterial hypertension (PAH).
Viagra Viagra well known because of its
appearance it is used to treat Erectile
Disfunction. It was developed and marketed by
Pfizer after seen as a side affect in clinical
trials for hypertension (high blood pressure). It
works by inhibiting cGMP specific
phosphodiesterase type 5 an enzyme that regulates
the blood flow in the penis. Mechanism of
action Sexual stimulation causes increased
release of nitric oxide (NO) from
non-cholinergic, non-adrenergic parasympathetic
nerve (NANC) endings in the walls of the arteries
and sinusoids of the penile corpora cavernosa.
Nitric oxide diffuses into the vascular smooth
muscle cells of the walls of the arteries and
sinusoids and stimulates cytoplasmic guanylyl
cyclase to increase cGMP production. Increased
levels of the cGMP cause the relaxation of the
smooth muscle cells supplying the corpus
cavernosum with blood. This increases the blood
flow to the penis and expansion of the corpus
cavernosa, which restricts the outflow of venous
blood resulting in an erection from the pressure
in blood. Since PDE5 is the principle enzyme
responsible for the decomposition of cGMP in the
corpus cavernosum, it is reasonable to expect
that inhibition of it results in the increase of
cGMP concentration, leading to enhanced smooth
muscle relaxation and improvement in erections
Unlike Viagra which is used in 25, 50 and 100mg
in occasional doses, Revatio is dosed in 20mg
amounts to be taken three times a day as it only
has a half life in the body of four hours. It
comes as small white round tablets unlike
Viagra's well known colour blue and also can be
administrated via injection.
Competition There is always competition from
other companies as in 2000 the annual sales
exceeded 1 billion dollars and accounted for 92
percent of ED sales in 2007. This percentage
dropped due a few factors including the main
compeptitors are Tadalafil (Cialis) and
Vardenafil (Levitra) entering the market and
counterfeits.
Tadalafil trade name Cialis is known as the
weekend drug as it can be effective for up to 36
hours as its half life is 17.5 hours and only
needs to be dosed at 5, 10 and 20mg. It came onto
the market by Eli Lily in 2003 and also was
approved in May 2009 for the treatment of PAH in
a dose of 40mg called Adcirca. Tadalafil inhibits
PDE6 the least compared to sildenafil and
vardenafil deceasing chance of vision side
affects.
The first step of the synthesis is the reaction
of a diketoester (1) and hydrazine to give the
pyrazole ring. The regioselective N-methylation
of the pyrazole and hydrolysis gives a carboxylic
acid (3). Compound (3) is then reacted with HNO3
and H2SO4 to give a nitrated product. This is
then followed by a carboxamide formation and the
reduction of the nitro group. The compound (4) is
then acylated under basic conditions and this
produces the pyrazolopyrimidinone (6). (6) is
then chlorosulphonylated selectively on the
5'-position of the phenyl ring. This can then
couple with an amine to give sildenafil (7).
Tadalafil
Vardenafil trade name Levitra when sold by Bayer
and sold by GSK as Vivanza. Very similar
structure to sildenafil with exceptions to the
nitrogens and side chains it has a longer time in
the body than viagra so only needs to be dosed in
2.5, 5, 10 or 20mg doses. Vardenafil is the only
one of the three not also approved for treatment
for PAH also in rare cases it has been found to
cause damage to the penile tissue leading to
permanent impotence.
Side affects The most common side affects
include headache, flushing, dyspepsia, nasal
congestion and impaired vision, including
photophobia and blurred vision. Some users have
found to see everything in tinted blue
(cyanopsia). This is caused by inhibiting
slightly the PDE6 which affects vision in rare
cases it has lead to vision impairment. Other
side affects in rare amounts include heart
attacks, stroke, severe hypertension and sudden
loss of hearing.
Vardenafil
References used for Information
include Medicinal Research Reviews, Vol. 26, No.
3, 369-395, 2006 Nature Reviews, Drug Discovery,
Vol. 5, Aug 2006 Bioorganic and Medicinal
Chemistry Letters, Vol.6, No. 15, pp. 1819-1824,
1996 Pfizer web pages Wikipedia
2
Omeprazole A Case Study
6-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl)m
ethylsulfinyl-1H-benzimidazole
Introduction
Synthesis/Manufacture
Physical Properties
Omeprazole is a highly effective compound that
inhibits gastric acid secretion and is indicated
in the treatment of acid-related disorders such
as Gastroesophageal Reflux Disease (GERD), peptic
ulcers and Zollinger-Ellison syndrome. Unlike the
histamine H2-receptor antagonists, such as
Cimetidine, Omeprazole works by inhibiting the
HKATPase in the proton pump of the gastric
parietal cells.

• Lipophilic - Easily penetrates cell membranes
• Weak base - Concentrates in acidic compartments
  of parietal cell
• Unstable in acidic solution Readily converts
  to active species
• Half life (Olbe, 2003)
• At pH1 2 minutes
• At pH7.4 20 hrs
• Blood plasma 1-2 hrs
• Site of action 24 hrs

Lead Generation
Astra was interested in developing an
antisecretory drug and a search of the literature
in 1972 discovered the compound CMN 131 (by
Servier) (Figure 1).
However the compound showed severe acute
toxicity. Astra believed the thioamide group to
be responsible.
Safety/Toxicology
The thioamide group was eliminated by
incorporating it between heterocyclic rings and
the first hit showed no acute toxicity. The
product was benzimidazole H124/26 (Figure 2).

• The MSDS data for Omeprazole shows that it is an
  irritant to the skin, respiratory organs and the
  eyes.
• Drug interactions
• Drugs for which gastric pH can affect
  bioavailability (Ketoconazole, Digoxin)
• Drugs metabolized by cytochrome P450 (CYP)
• Drugs eliminated by the liver (Warfarin,
  Diazepam, Phenytoin)

H124/26 was found to be under a Hungarian patent.
The sulphoxide metabolite H83/69 was found to be
even more potent and was not covered by the
patent. The new lead compound was named
Timoprazole (Figure 3).
Figure 5 Synthesis of omeprazole (Saunders, 2000)
Mode of Action
In long term toxicological studies Timoprazole
was found to cause enlargement of the thyroid
gland due to inhibition of Iodine uptake. Further
testing found compound H149/94 which showed
antisecretory action without effects on the
thyroid. The new lead compound was named
Picoprazole (Figure 4).
In order to suppress gastric acid secretion,
Omeprazole forms a stable disulfide bond with the
sulfhydryl group of the HKATPase this prevents
the final transport of hydrogen ions (via
exchange with potassium ions) into the gastric
lumen.
Conclusion
Omeprazole is a racemate composed of a 11
mixture of R and S isomers. Further research at
AstraZeneca looked at many variations of the
substituted benzimidazole and only one compound
showed greater activity than Omeprazole. This was
one of its optical isomers the S isomer or
Esomeprazole. A lot of research is currently
being carried out into the effects of long term
use of proton pump inhibitors including
omeprazole. It is hypothesised that extended use
of PPIs leads to a decrease in bone density due
to reduced calcium uptake from the small
intestine (Bratanic, 2009).
Figure 1 CMN 131
Figure 2 H 124/26
Figure 4 Picoprazole
Figure 3 Timoprazole
Lead Optimisation
References
In order to maximise accumulation of the drug
within the parietal cells, substituents were
added to the pyridine ring of Timoprazole., The
resulting compound was H 168/68 named Omeprazole.
This compound increased the rate of conversion
to the active species and is more stable to
conversion at neutral pH in comparison to
Picoprazole.
Bratanic, A. Kokic, S. Hozo, I. Barisic, I.
Kokic, V. Long-term therapy with proton pump
inhibitors is associated with decreased bone
density. Medical Hypotheses. (2009). 72.
608-609 Olbe, L. Carlsson, E. Lindberg, P. A
proton pump inhibitor expedition The case
histories of Omeprazole and esomeprazole. Nature.
(2003). 2. 132-139 Saunders, J. 2000. Top Drugs
Top Synthetic Routes. US Oxford University Press
Figure 6 Proton pump inhibition (Olbe, 2003)
Jo-Ann Daniells N0099034 Advanced Medicinal
Chemistry 27 April 2013