January 1999, Chemistry in Britain.

Making the Love Drug

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 Rhne-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,
Further information

Visit the Pfizer website at www.viagra.com

Science, 1998, 258, 1861.
European patent 0463756, 1992.