Sildenafil
Revatio
Synthesis of Sildenafil
The Blue and White Pill
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.
By Verity Jane Litchfield
Sildenafil citrate more commonly known as Viagra the erectile dysfunction (ED) treatment but
also marketed as Revatio a treatment for pulmonary arterial hypertension (PAH).
O
O
O
N2H4/H2O
OEt
(1)
H
N
(2)
N
EtO
O
nPr
Viagra:
Nanc
nerves
(i) Me2 SO4
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.
Nitric
oxide
(ii) NaOH/H20
N
HO
OEt
Synthesis of
cGMP
N
NH
1989
NaOH
EtOH/H2O
nPr
N
OEt HN
N
nPr
N
(5)
nPr
(6)
N
Nitric Oxide was described as
a neurotransmitter that’s
released during sex.
1990
Between ‘91 and 2000 research
reports the potential role of PDE5 in
the lungs vasculature: first
experimental use of other PDE5
inhibitors in experimental model of
PAH.
Sildenafil not further developed for
cardiovascular indications because of
relatively short life and potential
interactions with nitrates
1993
First studies in ED proving efficiency in
single doses of sildenafil in enhancing
erectile responses during sexual
stimulation
nPr
O2 S
Sildenafil (7)
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.
N
N
O
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).
Approval of Silenafil as Viagra
by FDA as first oral treatment
for ED
1998
N
N
(ii) N-Methylpiperazine
EtOH
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.
Formation of Research team
at Pfizer for selective PDE5
inhibitor
H 2N
(i) ClSO3H
Side affects:
1986
(4)
O
N
OEt HN
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
Sildenafil selected as candidate drug to
enter clinical development for
Cardiovascular indications
H 2N
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.
O
Sexual stimulation causes increased release of nitric oxide (NO) from noncholinergic, 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.
Erection
(iii) NH4OH
(iv) SnCl4
Competition:
Mechanism of action:
Increase of blood
flow in corpus
cavernosum
N
H 2N
OEt
Decomposition of
cGMP to 5’-GMP
Smooth muscle
relaxation
N
O
O
Et3N, DMAP
CH2Cl2
PDE5
(3)
nPr
Cl
Activation of
guanylyl cyclase
N
O
(i) HNO3/H2 SO4
(ii) SOCl2
O
2000
First Intravenous placebo-controlled
study evaluating effect of different
doses of sildenafil for PAH patients
First published case report on the
successful treatment of one patient with
primary PAH with chronic administration
of Sildenafil
Approval of Sildenafil as Ravatio for
the treatment of PAH by FDA and by
the EMEA.
N
N
H
O
Tadalafil
O
O
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.
O
O
N
O
S
N
HN
N
N
OEt
Vardenafil
References used for Information include:
End of Pfizer’s Viagra Patent
2005
N
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.
2011-2013
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
N
OMe
CH3
H3 C
O
N
N
Omeprazole: A Case Study
OMe
S
N
6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole
H
Synthesis/Manufacture
Introduction
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
H+K+ATPase in the proton pump of the gastric parietal cells.
Physical Properties
• Lipophilic - Easily penetrates cell membranes
i) MeLi, THF
ii) aq H2O2 , HOAc,
24hrs, 90o
N
OMe
i) HNO3, H2SO4,
heat
N
+
OMe
Ac2O, 110o
ii) MeOH, MeO-
N
+
O
O
i) MeOH, aq NaOH
reflux
Lead Generation
ii) DCM, Oo, SOCl2
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).
O
H2N
CH3
+
CH3
S K
+
O
N
S
HS
OEt
H2N
CH3
N
H
+
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).
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).
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).
S
MCBPA, CHCl3 ,
10 min, pH 8.6, 5o
CH3
H3C
O
H3C
N
S
N
O
N
H
O
CH3
CH3
H3C
O
H3C
N
S
N
N
O
Figure 5: Synthesis of omeprazole (Saunders, 2000)
Mode of Action
In order to suppress gastric acid secretion, Omeprazole forms a stable
disulfide bond with the sulfhydryl group of the H+K+ATPase this prevents
the final transport of hydrogen ions (via exchange with potassium ions)
into the gastric lumen.
in
acidic
compartments
of
• 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
Safety/Toxicology
CH3
N
H
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)
Conclusion
Omeprazole is a racemate composed of a 1:1 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.
S
N
H
Figure 1: CMN 131
Cl
H2O, NaOH, EtOH, Reflux 2hrs
N
NH2
N
H3C
O
H3C
However the compound showed severe acute toxicity. Astra believed the
thioamide group to be responsible.
N
OCOCH3
N
• Weak base - Concentrates
parietal cell
Figure 2: H 124/26
CH3
O
N
O
N
N
S
CO2 CH3
N
CH3
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).
S
N
H
Figure 3: Timoprazole
N
H
Figure 4: Picoprazole
Lead Optimisation
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.
References
Figure 6: Proton pump inhibition (Olbe, 2003)
Jo-Ann Daniells – N0099034
Advanced Medicinal Chemistry
13 April 2015
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
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