Viagra (Sildenafil Citrate) and erectile dysfunction drugs

It is estimated that 10 to 20 million American men suffer from impotence. One of the old treatments was simply inserting an internal splint into the penis, a desperate measure indeed. British neurophysiologist Giles Brindley investigated means of treating impotence by injections of drugs into the penis. He first found success by papaverine injection. He then began to experiment with phenoxybenzamine after a colleague of his told him about its effect in hypertension. In 1983, in the annual conference of the American Urological Association, Brindley literally “showcased” his success. A few minutes before his lecture, he went to the bathroom and injected phenoxybenzamine into his penis. During the lecture the 57-year-old British gentleman pulled down his pants to display his achievement and invited the audience to physically examine his erection!

Before the emergence of Viagra, the Food and Drug Administration approved Upjohn Company’s prescription drug alprostadil (Caverject) on July 6, 1995. Caverject, a member of the prostaglandin family, prostaglandin E1, was expected to successfully treat 70–80% of impotence patients. Inconveniently, Caverject has to be injected directly into the penis before sex, not the most romantic move. On the other hand, Viagra, an oral drug, achieves the same purpose without cumbersome injections. Serendipity played an important role in the discovery of Viagra. As Louis Pasteur pointed out, “Dans les champs de l’observation, le hazard ne favorise que les exprits préparés” (“In the field of experimentation, chance favors the prepared mind”). Recounting the story of Viagra may help us to better appreciate Pasteur’s point.

The saga began in 1985 when Simon Campbell and David Roberts, two chemists at Pfizer in Sandwich, England, put together a proposal to look for hypertension and angina drugs. They proposed to find compounds that would inhibit enzymes called phosphodiesterases (PDEs), which break down cyclic guanosine monophosphate (cGMP). At that time, little was known in the field of PDEs. One of the very few known PDE inhibitors was zaprinast, an antiallergy compound developed by May and Baker Laboratories (now part of Aventis). Zaprinast, a vasodilator, is not a clean drug-it inhibits PDE, as well as quite a few other enzymes. Theophylline is a PDE III and VI inhibitor, too. In order to make a better drug, one would need to find a more potent, more selective inhibitor that could be patented. One year later, the cGMP PDE approach received enough attention from management that five chemists were assigned to work on it, with Nicholas K. Terrett as the head of chemistry. Using zaprinast as the
starting point, the team did what medicinal chemists do best-structuralactivity relationship (SAR) investigation. By removing one nitrogen atom on the triazole ring, adding a sulfonamide group to reduce the molecule’s lipophilicity (greasiness), and adorning the molecule with a couple of substituents, they created UK-92480 in 1989. In all, the team made 1,600 compounds for this program in 3 years, quite a feat considering that combinatorial chemistry was not reported until the early 1990s. Despite doubts in the company that achieving selectivity among the various PDEs could have been achieved, UK-92480 was shown to be selective in inhibiting one of the PDEs, PDE5, with weak activities against other PDE enzymes. It is only tenfold selective for PDE5 against PDE6, an enzyme involved in visual transduction, which may account for some of the visual side effects that have been occasionally observed with Viagra-some men who take Viagra will experience temporary color changes in their vision and see things as blue or green. In order to improve solubility, Terrett prepared the citrate salt of UK-92480, which would become sildenafil citrate and later Viagra.

Nothing was unique about the story of Viagra thus far; it was just like any other drug discovery and development program. Things started to become interesting after the clinical trials began. Pfizer started Phase I clinical trials of sildenafil citrate in 1991 on healthy male volunteers and later commenced limited Phase II trials for indication of severe coronary heart disease (angina). Unfortunately, the drug was not efficacious for treating angina, and it was logical to terminate the trials. There is an urban legend that the healthy volunteers in Phase I trials refused to return tablets. In fact, the volunteers were in a clinical unit and did not have possession of the drugs. In further inquiries, some clever clinicians led by Ian Osterloh learned that the men “suffered” an unanticipated side effect, sometimes referred to in clinical trials as “unexpected benefits”: the drug catalyzed their erections. The effect was especially striking for patients on high doses; 88% of them reported improved erections. However, especially at this time, a drug firm’s ambition is to treat disease rather than to help healthy men achieve erections. Male erectile dysfunction is a serious disease, afflicting 10% ofmen under the age 40 but an astonishing 52% ofmen over 40 years old. In 1994, Pfizer initiated limited Phase II trials for 12 patients with male erectile dysfunction; 10 of them showed dramatic improvement in their erections, and the rest is history.

However, one problem still remained. Pfizer had been expecting sildenafil to be a small product for angina. It now had a major blockbuster for male erectile dysfunction on its hands. Manufacture of the drug by the original medicinal chemistry route could not keep up with the rapidly expanding clinical program. A new route of synthesis was urgently required. By April of 1995 the Chemical Research and Development team at Sandwich in the United Kingdom, led by Peter Dunn, had invented a new synthesis of sildenfil. Dunn had left school at the age of 16 to work in a local chemistry factory. In 1984 he quit his job to study with Charles Rees at Imperial College, London, who helped him in his chemistry career. During the summer of 1995 the new synthesis was scaled up from 10 g to 1000 Kg in 13 hectic weeks to keep the clinical program on track. In 1996 Pfizer filed for a patent covering the new manufacturing method, with Peter Dunn and Albert Wood as inventors. The new synthesis gave an overall yield of 66% from 2-pentanone, which was an order of magnitude greater than the previous method.

On March 27, 1998, the FDA approved sildenafil citrate (trade name Viagra) for the treatment of male erectile dysfunction, and 4 million prescriptions were filled within the first 6 months. The sales reached $411 million in the first 12 weeks. Since its emergence, Viagra has received unprecedented publicity. The inventors found themselves being invited to do TV interviews and unexpectedly finding their pictures on the front page of national newspapers. Viagra, the little blue pill, has penetrated the cells of pop culture. It is one of the most commonly recognized names worldwide.

Viagra’s mechanism of action is closely related to that of nitric oxide. Sexual stimulation leads to the release of nitric oxide within the blood vessels of the penis, where it stimulates guanylate cyclase to increase cGMP levels in the corpus cavernosum. There are high levels

of PDE5 in the corpus cavernosum of the penis, and PDE5 is able to degrade cGMP and cause termination of erection. Nitric oxide production may be impaired in patients suffering from erectile dysfunction, leading to low levels of cGMP, which can be quickly degraded by PDE5. Inhibition of PDE5 by Viagra slows the breakdown of cGMP, allowing for higher concentrations of cGMP to build up in the corpus cavernosum, leading to an erection. Here is where it gets tricky: because nitroglycerin taken for heart conditions works via the nitric oxide production pathway as well, Viagra is contraindicated to nitroglycerin. Therefore, patients taking nitroglycerin or similar drugs should not take Viagra because the peripheral vasodilation from nitrates plus Viagra will divert blood away from a heart that is already compromised and will lead to further damage from lack of coronary blood flow. To overcome such a caveat, sexual dysfunction medicines using other mechanisms are desired. A cyclic peptide nasal spray, PT-141, stimulates melacortin receptors and was successful in Phase II clinical trials for erectile dysfunction and female sexual dysfunction.

On the heels of Viagra, two additional male erectile dysfunction drugs, Levitra and Cialis, emerged in 2003. Similar to Viagra, Levitra has a halflife of about 4 hours. Cialis’s half-life is much longer, at 17.5 hours.

Riding on the commercial success and immense publicity of Viagra for men’s erectile dysfunction, Pfizer invested millions of dollars and 8 years of clinical trials that involved 3,000 women in studying female sexual dysfunction. In the end, the results were equivocal. Not surprisingly, men and women display fundamentally different relationships between arousal and desire. For men, arousal invariably leads to desire, whereas arousal in many women has little effect on a woman’s willingness, or desire, to have sex. In one trial, clinicians used a pelvic probe to measure any change in genital blood flow while women sat in front of erotic movies. Sure enough, the sex organs of women given Viagra were more engorged than those given placebo. The only problem was that, although Viagra was associated with greater pelvic blood flow, women experiencing this effect did not feel any more aroused. Mitra Boolell, leader of Pfizer’s sex research team, pointed out that there is a disconnect in many women between genital changes and mental changes. This disconnect does not exist in men. With women, things depend on a myriad of factors. The bottom line is that the brain is the primary sex organ for women, and the genital area is only a secondary sex organ. In addition, hormone level seems play a more important role than blood flow.