January 1999, Chemistry in Britain.
How do you
turn a possible treatment for angina into a world-renowned anti-impotence
drug? Elizabeth Palmer looks at the story behind the drug that is
commanding international attention
On 27 March 1998, the US Food
and Drug Administration approved a new drug for treating male erectile
dysfunction (MED). Since then the drug has achieved record sales and has
been the subject of extraordinary media interest, becoming a household name
in the few months that it has been available. The drug is of course Viagra,
more scientifically known as sildenafil citrate. But behind all the media
hype is a drug with serious potential. MED affects an estimated 10 per cent
of men - a figure that leaps to an incredible 52 per cent of men aged 40 to
70 years. Viagra is the first oral anti-impotence drug to offer them hope.
The story of viagra's discovery
is an interesting one. Viagra started life as a potential treatment for
hypertension, and then angina. So how did the Pfizer team who discovered
the drug at the company's Sandwich site in Kent,
UK,
make the sideways step to such a highly successful drug for impotence?
The discovery programme began in
1985 when Simon Campbell and David Roberts, both chemists at Pfizer, wrote
a proposal to look for antihypertensive and antianginal compounds that
would work by inhibiting phosphodiesterase (PDE). This intracellular enzyme
hydrolyses cyclic nucleotides such as cyclic guanosine monophosphate (cGMP)
- a vasodilator that relaxes the vascular smooth muscle of the blood
vessels, allowing increased blood flow. Nick Terrett joined the programme
in 1986 as head of the chemistry team. His team - made up of four chemists
including himself - was given the task of finding a compound that would
inhibit PDE.
The team began a typical
medicinal chemistry discovery programme to find a chemical starting point
that would be potent, selective, novel and ultimately effective. They
started by checking the literature to see if there were any compounds that
raised levels of cGMP by inhibiting PDE. One of the very few compounds
known at that time for inhibiting PDE was Zaprinast (1), which was
developed as an antiallergy compound, but hadnever been commercialised by
its developers, May and Baker (now part of Rhône-Poulenc Rorer). Zaprinast
is a vasodilator in vitro, but it isn't only a PDE inhibitor — it
works by a number of different mechanisms. 'There was other pharmacology
associated with Zaprinast. It wasn't selective or potent enough, and we
wanted a compound that was proprietary to Pfizer', Terrett says.
The team needed to find a
molecule that would bind to PDE's active site, so that it couldn't convert
cGMP to the inactive GMP form. They studied the structure of the substrate
cGMP as a starting point, hoping to find some clues as to how they might
modify the chemical structure of Zaprinast to make it more selective and
potent. By exploring other ring systems, the team found that some had
improved activity over Zaprinast, such as the pyrazolopyrimidinones (eg
2). The researchers substituted a propyl group for a methyl group on
the pyrazolopyrimidinone system to increase affinity for PDE and give a more
potent compound. They then added a sulphonamide group to reduce
lipophilicity and increase solubility. The resulting compound was later to
become known as Viagra, but in 1989 was known by the team simply as UK 92480 or
sildenafil (3).
In all, about 1600 compounds
were made over the lifetime of the project. 'This was in the days before
high throughput screening and combinatorial chemistry. With hindsight we
could have made some of the analogues more rapidly using a parallel
synthetic technique, but this wasn't commonly practised at the time',
Terrett says. It was a high level technical challenge, and according to
Gill Samuels, also a member of the Viagra discovery team, 'there was a lot
of ground-breaking work to be done because there wasn't a great deal of
confidence in the company that we could get a really potent and selective
inhibitor'.
Pfizer started Phase I clinical
trials of sildenafil in healthy volunteers - ie men who had no
history of coronary heart disease - in July 1991. The volunteers were given
increasing quantities of the drug to see how well they tolerated it and if
there were any side effects. The following year, two things happened in
parallel, changing the direction in which the discovery team were heading
with the drug. Sildenafil had progressed to a limited Phase II trial in
patients who had severe coronary heart disease (angina), but it did not
fulfil the team's expectations in terms of its activity. However, a further
Phase I study was being carried out at the same time, which was intended to
push sildenafil to its limits. This was a 10 day multiple high dose study
to observe how much of the drug could be given to the volunteers without
incurring side effects. Because it was a high dose level, the volunteers
did report side effects, including headache, indigestion, visual
disturbance, muscle ache - as well as a change in erectile function.
A curious
side effect...
For the discovery team this
change in erectile function was an interesting phenomenon; it fitted their
data and the literature sufficiently for them to wonder if it could occur
at a single dose of 100mg. 'Remember that at this point there was no
certainty it could be a useful treatment for erectile dysfunction (ED)
because the dose was too high', says Terrett. The team also knew that
getting such an effect in normal volunteers didn't necessarily mean that it
would happen in men with ED.
Because the drug did not look
promising for treating patients with coronary disease, the team debated the
possibility of using sildenafil as a therapeutic drug for MED. It took much
deliberation to come to the decision - there were still many questions to
be answered about how sildenafil worked - but eventually the team decided
to change direction and put sildenafil on trial as a drug for MED. 'There
was no eureka moment', says Terrett. 'It was by no means guaranteed at this
point that it would lead to a drug for ED'.
But the pieces of the jigsaw
were starting to come together. In 1992 Science named nitric oxide
(NO) 'Molecule of the year', and researchers were beginning to understand
the role of NO as a signalling molecule in the body - a discovery that has
been recognised in last year's Nobel prize for medicine (Chem. Br.,
November 1998, p29). 'There was now a potential mechanism to underwrite what
we thought might be happening in the Phase I trials', says Terrett (see
Box 1). 'A phenomenon with no mechanism attached makes people feel
nervous, particularly when it's to do with something like erectile
function'.
...causes
excitement
In May 1994 Pfizer began the
first Phase II trial of sildenafil in men suffering from ED. It was a
limited trial using only 12 patients with ED. But 10 out of the 12 patients
showed improved erectile function, and according to Terrett 'there was a
lot of excitement at that point'. The next step was to take the drug out of
the clinic and into the home setting - a more natural environment for
assessing the drug - which happened between September 1994 and February
1995. During this outpatient trial the team came up against the problem of
how to do a clinical trial for ED in the home; there was no precedent. So
they developed the International Index of Erectile Function - a sexual
function questionnaire that the patient fills in to give some
quantification of the degree of ED and the benefit of taking the drug -
which has now become the standard for assessing ED. 'This was critical
because it meant we now had the same benchmarks for clinical trials in
different countries', says Terrett.
There were a lot of changes in
direction along the way and an element of uncertainty, similar to most drug
development programmes. As Samuels wryly comments, 'People always look back
at these programmes and think that every turn we took had a clear signpost
on it saying "This way to marvellous efficacy", but in fact there
is often a fork in the road. At every fork we came to as we moved forward
with Viagra, we probably chose the most challenging route to make sure we
got the highest quality answer'.Patients were asked to keep a
daily diary and to respond to the questionnaires: there was encouraging
feedback (Fig 1). Then it was a case of starting 'open-label'
studies where people knew what it was they were taking; 36 centres -
usually the urological departments of hospitals - were involved in the UK,
France and Sweden, assessing 225 patients over 32 weeks. At the end of the
trial 88 per cent of patients reported that sildenafil had improved their
erections and just over 90 per cent wanted to continue with the treatment.
Of those that withdrew, less than 4 per cent gave lack of efficacy as the
reason, and 4 per cent because of adverse effects (headache, indigestion).
'We were finding that we could get efficacy at a single dose and that there
was a dose-response effect, and if there's anything that gladdens the heart
of a pharmacologist it's getting a dose-response relationship', says
Samuels.
Viagra has now helped over 3
million people worldwide to overcome impotence, a condition that has a
significant impact on the quality of life for many men and their partners.
But the Pfizer team are not finished yet. 'Clearly with a drug like Viagra
you don't rest on your laurels', says Terrett, adding 'We understand the
drug extremely well now and will continue to look for improvements. We have
received dozens of letters from men who have been helped by Viagra and this
is what makes it all worthwhile'.
Box 1. How Viagra works
Sexual stimulation leads to the
local release of nitric oxide (NO) from nerve endings and endothelial cells
in the spongy erectile tissue — the corpus cavernosum — of the penis. NO
switches on the enzyme guanylate cyclase, which converts guanosine
triphosphate into cyclic guanosine monophosphate (cGMP). This key second
messenger is a vasodilator — it relaxes the vascular smooth muscle of the
blood vessels of the corpus cavernosum, so that the blood flows more
strongly leading to an erection. However, at the same time cGMP is
hydrolysed by phosphodiesterase type 5 enzyme (PDE5), to inactive GMP.
Men who have erectile
dysfunction (ED) are often producing insufficient amounts of NO. So
although they are producing a small amount of cGMP, it is being broken down
at the same rate. Viagra works by blocking part of the cycle. It
selectively inhibits the PDE5, by binding with PDE5's active site. This
prevents the hydrolysis of cGMP to inactive GMP, allowing cGMP to accumulate
and prolong the vasodilation effect.
Because of this mechanism of
action, Viagra works regardless of the underlying cause of ED. It is
effective in men with ED associated with a variety of medical conditions,
including vascular and neural disease, diabetes, prostate surgery,
depression and spinal injury (providing sufficient nerve has been left
intact). Whatever the cause of reduced NO formation, Viagra still works.
However, Viagra is not an aphrodisiac. Because the drug is potentiating the
natural effects of cGMP rather than stimulating its production, it only
works in response to sexual stimulation.
How NO
mediates erections
At present, 1400kg of highly
concentrated pure sidenafil citrate is made each week by an automated
process in a factory in Ringsakiddy, Co Cork,
Republic of Ireland. Making one batch of the
drug takes 21 days. The Scheme below shows the original 'discovery'
route used to synthesise sildenafil. Commercial manufacture of the drug is
by an alternative route, the details of which are strictly under wraps.
The resulting white crystalline
powder is taken to one of three centres - in France,
Puerto Rico or the US
- where it is diluted with inactive ingredients: microcrystalline
cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium,
magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide,
lactose and triacetin. The powder is then coloured blue, and formulated
into the characteristic rounded-diamond-shaped tablets equivalent to 25mg,
50mg and 100mg of sildenafil.
Pfizer aims to start producing
the drug at its plant in Sandwich, Kent, for sales in Britain in
the year 2000.
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