Illustration of the male reproductive system


22/9/04. By Richard Twyman

Viagra (also known by its generic name sildenafil) is a small-molecule drug used to treat male erectile dysfunction.

The disease

When a man is sexually aroused, his penis enlarges and becomes erect. This is caused by increased blood flow into the penis and restricted blood flow out of it. An occasional failure of this natural response is quite normal. It can be caused by tiredness, anxiety, illness or certain medications. However, about 10 per cent of men find it difficult to get an erection at any time. The incidence of this disorder, which is known as male erectile dysfunction or impotence, increases dramatically with age.

Up to 50 per cent of men over 40 suffer from persistent erectile dysfunction (failure of erection at least one in every four times that intercourse is attempted) while about 35 per cent have complete erectile dysfunction and thus find it impossible to become aroused at all.

For a long time, impotence was considered to have a predominantly psychological basis, but it is now thought that the majority of cases have a physical cause.

The target

Sexual stimulation causes cells and nerve endings in the erectile tissue of the penis to release a substance called nitric oxide. The nitric oxide activates a dormant enzyme, which produces an important signalling molecule called cyclic GMP (cGMP). This molecule is a vasodilator – it relaxes the smooth muscles surrounding the blood vessels at the base of the penis, allowing stronger blood flow and leading to an erection.

However, there is another enzyme called phosphodiesterase whose function is to break down cGMP. Men with erectile dysfunction often produce too little nitric oxide, which means not enough cGMP is made.

The little that is made is rapidly broken down by phosphodiesterase and blood flow is reduced, resulting in erectile failure.

The drug and how it works

Viagra is a small molecule that mimics the shape of cGMP, the natural substrate of the enzyme phosphodiesterase. All enzymes possess what is known as an active site, which is where the chemical reaction controlled by the enzyme actually takes place. If that site is blocked somehow, for example by inserting a molecule that has a similar shape to the normal substrate but which cannot be broken down, then the enzyme is unable to work.

When Viagra binds to phosphodiesterase, the enzyme is unable to break down cGMP, allowing it to accumulate in the blood. As Viagra targets one of the final steps in the pathway of erectile function, it can be used regardless of the underlying cause of the disorder (such as injury, surgery, disease or depression). What Viagra does not do, however, is act as an aphrodisiac; sexual stimulation is still required.

How Viagra was developed

The development of Viagra is an interesting example of rational drug design, based on the structure of a known ligand. The story began in 1985 when two scientists at Pfizer wrote a proposal to find new drugs for the treatment of high blood pressure and angina. The idea was to inhibit the enzyme phosphodiesterase, which would lead to an increase in the amount of available cGMP, resulting in vasodilation.

Background: Rational drug design

A strategy was devised in which new chemical entities would be designed based on the structure of cGMP, as such molecules would be expected to block the enzyme's active site. Over 1000 different compounds were synthesized and tested, and the one with the most promising activity was submitted for clinical trials.

No serious side effects were found in the phase I clinical trials (with healthy individuals) and the testing progressed to phase II trials in patients with severe angina. The results were disappointing. However, further phase I trials carried out at the same time with high doses of the drug revealed some interesting side-effects, including frequent erections in the male participants. The research team switched direction and tested the drug as a possible treatment for impotence.

In the first trial, in 1994, ten out of the 12 patients reported an improvement in erectile function. Further trials were carried out on a larger sample, and again about 90 per cent of the patients reported an improvement. The drug was finally licensed in 1998.

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