Viagra discovery

Very often, drugs are discovered through persistent work and continual optimization and many tests and trials. This is exemplified by the history behind the discovery of sildenafil (Viagra, Pfizer), a drug for the treatment of erectile dysfunction, and the AIDS drug zidovidine (Retrovir, GlaxoSmithKline) (Exhibits 3.18 and 3.19). 

The long, tortuous path from drug discovery to commercialization is amply demonstrated by the sildenafil (Viagra) story. 

An entire new field of therapeutics arose with the serendipitous discovery of the effect on erectile function of sildefanil (see Chapter 15), far better known as Viagra . The enormous and still rising market opened by that drug has predictably led to the search for other inhibitors of phosphodiesterase 5, the enzyme responsible for this activity. The stmctures of many follow-on agents have hewed fairly close to the original PDE 5 inhibitor. Others, such as avanafil (58-9), differ markedly from sildefanil in structure. The synthesis of this agent in effect consists of a series of displacement reactions. Thus, reaction of the benzylamine (58-1) with chloropyrimidine... 

This discovery and its subsequent development led to Viagra as well as the 1998 Nobel Prize in Physiology or Medicine to R. Furchgott, F. Murad, and L.J. Ignarro. 

Another recent example is provided by the discovery of the use of sildenafil (Viagra Fig. 1.15), a phosphodiesterase type 5 (PDE5) inhibitor, as an efficacious, orally active agent for the treatment of erectile dysfunction [25,26]. Initially, this compound was brought to the clinic as an hypotensive and cardiotonic substance, but its usefulness in erectile dysfunction resulted unexpectedly from clinical observations made during a 10-day toleration study in Wales [27]. 

Kling, J. From hypertension to angina to Viagra. Mod. Drug Discovery 1988, 31-38. 

The discovery of its role as a useful chemical of the body has also led to the development of the anti-impotency drug viagra. 

Campbell, S.F., Science art and drug discovery a personal perspective. Clinical Science, 99,255, 2000. Brock, G., Sildenafil citrate (Viagra ), Drugs of Today, 36, 125, 2000. 

Dr David Brown, Managing Director of Alchemy Biomedical Consulting, Ltd., co-inventor of Viagra (sildenafil), and former Global Head of Discovery Research at Roche, when asked whether the downturn in NDA approvals is a concern for pharmaceutical profitability in the long term replied, Yes, both in numbers and quality. ... 

One of the celebrated illustrations of serendipity in drug discovery has to be the cis-platin drugs. Turning off the current did not kill the interesting therapeutic effect on tumor cells, and some alert scientists found the reason why. Penicillin, barbiturates, and more recently Viagra definitely underline the case for serendipity as a metric in drug discovery. 

In synthesis, the fewer steps, and the more steps that can be carried out without change of solvent, the better. Reichardt andWelton (2011, p. 512) mention two major successes in reduction of solvent use by Pfizer an amazing 180-fold reduction in solvent use in the synthesis of Viagra from discovery to the final, optimized scheme (Dunn et al, 2004), and the three steps in different solvents with isolation of intermediates at each stage in the synthesis of sertraline done all in ethanol with isolation of the final product only (Taber et al, 2004). 

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