Sildenafil

In 1998, it was quite unusual for a chemical compound became a headline in many media because of this compound. This compound was made by Pfizer and it was intended to be a heart drug but it turned out to help impotent men to have better active sex lives. This compound is called sildenafil which is the active ingredient in Viagra.

Sildenafil

Sildenafil was synthesised by a group of pharmaceutical chemists who was working at Pfizer research centre in Kent, UK. It was intended to be used for hypertension and angina pectoris, both of them are heart diseases. During the phase I clinical trials in Swansea, it was found to have small effect on angina but it could induce marked penile erection. Therefore, Pfizer marketed as treatment for erectile dysfunction rather than angina. Then, it was patented in 1996 and it was approved in 1998 by FDA for erectile dysfunction. In 2010, the annual sales of sildenafil in USA reached $1.928 billion and make it the 6th best selling drugs by Pfizer in that year.

Pfizer developed the synthesis of sildenafil which comprises of 9 steps, including the formation of pyrazole acid and cyclisation as shown below.

Sildenafil synthesis

The first step of this synthesis was the formation of 1,3-diketone which is the precursor compound for the pyrazole formation. Then, the methyl pyrazole 4 formation is interesting to see because it was synthesised using hydrazine followed by methylation rather than using methyl hydrazine H₂NNHMe.

The reason behind these steps is the use of unsymmetrical diketone can lead to selectivity problem which would lead to lower yield of 4. Besides that, the methylation is also regioselective and it prefers the N atom pyrrole-like because it would have the longest conjugated system involving the N atom and carbonyl ester. Another interesting point to make in this synthesis is the easiness of the formation of the second heterocylic ring in 9 which has the formation of another aromatic ring as its driving force. This reaction would not happen unless the product is a stable aromatic compound.

Mechanism of action of sildenafil

This compound works by protecting cyclic guanosine monophosphate (cGMP) from degradation by an enzyme which is called cGMP-spesific phosphodiesterase type 5 (PDE5). Sildenafil is quite effective for this mechanism because it is a selective inhibitor. Furthermore, sildenafil is broken down by liver and the major product of metabolism is metabolised further and excreted mainly in faeces and lesser extent in urine.

Besides its function as erectile dysfunction treatment, it also has many functions which might related closely to heart function. Sildenafil is commonly used by mountain climber for the prevention and treatment of pulmonary edema related with altitude sickness. One of the examples of this was explained Jeremy Clarkson from Top Gear when three presenters tried to climb the Guallatiri volcano which featured in the "Bolivia Special" episode and it seemed not working at all.

Another use of sildenafil is it might help to treat jet lag recovery and it was shown in hamster by Patricia V. Agostino, Santiago A. Plano, Diego A. Golombek from Argentina. This research was published in the Proceedings of the National Academy of Science and also was awarded 2007 Ig Nobel Prize.

Some of the dark sides of Viagral are it is sometimes used as unprescribed recreational drug, some of the cases it is mixed with MDMA or opiates to compensate the common effect of erectile dysfunction. The other dark side of sildenafil, although it is still disputed, is cutting the job of "fluffer" in the "gentlemen special interest" industry and this is due to the function of "fluffer" and Viagra is almost the same. However, as mentioned earlier, it is disputed because some of the figures in that industry claimed they don't exist.