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Viagra (sildenafil citrate) changed the standard for erectile dysfunction therapy by providing millions of frustrated men with an alternative to available treatments – injections, implants, and pumps – that seem more likely to kill the mood than to fix the problem.

But Viagra did not appear overnight. From its birth in 1989 in Sandwich, England, as compound UK-92,480, Viagra traveled the tortuous journey that all prospective drugs must follow. A desire for a new antihypertensive launched the effort that would produce Viagra, and angina pectoris later drove its development. The compound lost its way when it proved to be ineffective as an antianginal, and only good luck and sharp-eyed clinical investigators saved it from the scrap heap of dead-end drug candidates.

The hypertension years

Viagra wasn’t even a glimmer in Pfizer chemist Nick Terrett’s eye when he joined a project in 1986 to help develop a lead compound for the treatment of hypertension. His project was based on an idea that Pfizer scientists Simon Campbell and Dave Roberts had proposed the year before. The hot molecule of the day was atrial natriuretic peptide (ANP), and Terrett’s team was seeking compounds that would increase ANP’s natural activity. ANP causes the kidneys to release sodium and increase urine flow, making it a natural diuretic. It also causes the smooth muscle cells of blood vessels to relax, which increases blood flow and lowers blood pressure. Terrett’s project was conceived with the idea that a drug that would increase ANP activity would be a powerful new treatment for high blood pressure.

Rather than trying to administer ANP or an ANP mimetic, Campbell and Roberts proposed augmenting ANP activity with a drug that would manipulate the secondary intracellular signals that occur when ANP binds its receptor. ANP receptor binding activates guanylate cyclase, allowing it to convert guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The general cellular response to a buildup of cGMP levels is to reduce the amount of free intracellular calcium, either by flushing it from the cell or sequestering it within. The physiological consequence of decreased calcium depends on the location and function of the cell. In platelets, which cause blood clots, the result is platelet deactivation. In the kidney, the result is smooth muscle cell relaxation and release of sodium. Elsewhere, vascular muscles relax and allow blood vessels to fill with more blood, lowering overall blood pressure.

Levels of cGMP are held in balance by enzymes known as phosphodiesterases (PDEs), which convert cGMP into GMP by breaking the cGMPÕs cyclic phosphate ring. GMP is subsequently converted to GTP by another enzyme, completing a cycle: from GTP to cGMP, then GMP, and finally back to GTP. It was the PDEs that Terrett and his team decided to target for drug development, reasoning that a PDE inhibitor could prevent the breakdown of cGMP created in response to ANP. cGMP concentrations would then increase, thanks to PDE inhibition, and if in response smooth muscle cells in the kidney and blood vessels did their part and relaxed, blood pressure would drop. And Pfizer might have a winner in the hypertension market.

Viagra was discovered

Terrett et al. launched their search for a PDE 5 inhibitor with the choice of Zaprinast as their chemical starting point (1). Zaprinast was one of the very few cGMP PDE inhibitors known in 1986, albeit one that was weak and nonselective. Originally developed as an antiallergy compound, it is a vasodilator in vitro and lowers blood pressure in anesthetized dogs.

Noting that the heterocycles on Zaprinast and cGMP had similar sizes and shapes, the team explored a large variety of ring-system substitutes for the Zaprinast heterocycle. They tested their new compounds for improved affinity and selectivity by using in vitro PDE enzyme-inhibition assays. Later, they had to make substitutions elsewhere in the improved inhibitor to maximize solubility and reduce lipophilicity. The end result, UK-92,480, or Viagra (sildenafil citrate), selectively inhibited PDE 5. In a canine coronary artery assay, Viagra elevated cGMP and left cAMP levels unchanged, which would be expected of a PDE 5 inhibitor. Pharmacokinetic data for Viagra in humans and dogs were very similar.

IC50 values for PDE inhibition assays

PDE 1PDE 3PDE 5
Zaprinast9.4 µM58 µM2.0 µM
UK-92,480260 nM65 µM3.6 nM

aEnzymes of animal origin 

Reference
(1) Terrett, N. K. et al, Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824.

But that reasoning was oversimplified. To succeed, the project would have to consider what was being learned about the PDEs. Five distinct PDE subtypes (now up to nine) were known then, not all of which acted on cGMP. PDE 4, for instance, breaks down another secondary messenger, cyclic adenosine monophosphate (cAMP). Clearly, inhibiting the wrong PDE subtype would kill the project. However, inhibiting the right PDE subtype, without doing so selectively, might cause too many side effects. It was also known that different PDE subtypes occur in different tissues, so Terrett’s team would have to look for a lead compound targeting a PDE in the kidney.

The team, made up of Terrett and chemists Andy Bell and David Brown (now of Glaxo), was initially hindered by a lack of good assays. “In the early days, we were dealing with isolated strips of rat aorta, looking for relaxation in response to test compounds,” Terrett recalls. But tissue-based assays proved too difficult to replicate and interpret with confidence. The project really took off about a year after it began, when biologist Frank Burslem isolated PDEs from rat kidneys and rabbit platelets. Inhibition assays with Burslem’s enzymes gave clean, interpretable data.

The angina years

In 1988, chemistry began to dictate the project. As Terrett recalls, “We had compounds that were quite potent against PDE 5. One of our directors of biology suggested that because type 5 is prominent in vascular muscle cells, our PDE 5 inhibitor would be a vasodilator, and because PDE 5 is also in platelets, the inhibitor could prevent the formation of blood clots. This wasn’t a bad profile for a drug to prevent thrombosis. If you can increase blood flow to the muscles of the heart, you can treat angina.” Angina pectoris is defined as brief attacks of chest pain due to insufficient oxygenation of heart muscles; thrombosis is the formation of a blood clot inside a blood vessel.

Parallel biological evidence also supported changing the focus to angina. “As we gained a better understanding of the enzyme subtypes, we realized that PDE 5 wasn’t present in the kidneys,” recalls Peter Ellis, a senior clinical project manager at Pfizer Central Research in Sandwich and a project leader in the discovery biology laboratories at the time. With PDE 5 absent from the kidney, a PDE 5 inhibitor couldn’t be an ANP-enhancing antihypertensive.

Using enzyme inhibitor assays with PDEs 3 and 5 from rabbit platelets and PDE 1 from rat kidneys, the team focused on finding a molecule that would inhibit PDE 5 but not PDEs 1 or 3. They reached their goal in 1989 with UK-92,480. It was not the most selective of the compounds they had synthesized, but it had the best overall performance in preclinical testing. The clinic beckoned.

The Welsh observation explained

When the clinical trials began, UK-92,480 looked like a bust. It came through fine on safety tests in healthy volunteers, but in clinical pharmacodynamic studies in healthy volunteers, the drug did not have much impact. Data on changes in blood pressure, heart rate, forearm blood flow, venous compliance, and cardiac output were discouraging. “It was doing a lot less than clinical doses of nitroglycerine,” said Michael Allen, then clinical project manager and currently director of Pfizer’s early clinical research group. UK-92,480 was in dire trouble.

Viagra acts by inhibiting PDE 5

But it still had a pulse, thanks primarily to an observation that Allen received from one of the preceding safety trials – an early 1992 toleration study in the town of Merthyr Tydfil, Wales. In that study, healthy volunteers received three 25-mg doses per day for 10 days. Although the drug was well tolerated at a level of 25 mg, the volunteers reported some side effects at higher doses. Allen recalls a telephone conversation with the clinician who was running the trials: “He mentioned that at 50 mg taken every 8 hours for 10 days, there were episodes of indigestion [and of] aches in patients’ backs and legs. And he said, ‘Oh, there are also some reports of penile erections.’”

It was not a Eureka moment, as portrayed in some popular accounts, said Allen. “It was just an observation.”

Obviously, a crucial one. But it was not clear how important the effect was, and the participants did not report the erections until they were well into the 10-day trial period. “The decision to do the pilot studies [in erectile dysfunction patients] wasn’t that obvious. Erections hadn’t been reported until the 4th or 5th day, and there were other side effects as well,” said Ian Howard Osterloh, global candidate team leader for Viagra’s research and development group. Another factor favored pursuing the finding: Pfizer scientists thought that they could explain why UK-92,480 caused erections. If they were right, they had more reason to be confident that they might have stumbled upon a treatment for male impotence.

At the time, nitric oxide (NO) was receiving a lot of research attention because of its role as a signaling molecule. NO is an unstable, gaseous free radical that acts as an intercellular messenger. It has a wide range of physiological effects, including vasodilation, antiplatelet activity, modulation of neurotransmission, and immune defense against pathogens. Importantly for Pfizer, there were reports that NO also plays an essential role in penile erection. NO, like ANP, activates secondary signaling via cGMP. That suggested a hypothesis for how UK-92,480 might help impotent men: In men with erectile dysfunction, sexual stimulation released insufficient NO from the penile nerves.

As a result, cGMP was not building up to sufficient levels to relax the vascular muscles in the penis. Those muscles constrict the blood vessels used to fill the erectile chambers of the penis. When the muscles relax, the vessels dilate sufficiently for blood to fill the erectile chambers, causing an erection. If the NO deficiency hypothesis was true, it followed that by preventing PDE 5 from converting cGMP to GMP, UK-92,480 would cause cGMP in the penis to increase until the vascular muscles relaxed, blood flowed, and an erection resulted.

Terret uses an analogy of water going into a bathtub with an open drain to explain the drug’s effect, likening NO to the faucet, cGMP to water, and PDE 5 to the open drain. As Terrett explains, “In a normal patient, sexual stimulation turns the faucet on high enough that the bathtub fills quickly, for the water that drains away isn’t leaving fast enough to drain the water in the tub. An impotent man can’t turn the faucet on completely.” So, rather than turning the impotent man’s faucet wide open, UK-92,480 plugs the drain, allowing the tub to fill.

Of course, none of these mechanisms were clearly understood at the time the angina trials were performed. But in light of the scientific literature about NO and penile erections, Allen and others viewed the reports of the erection side effect as important enough to pursue.

Would the team have decided to follow it up if there had not been a mechanistic explanation for the side effect? “I don’t know. I think there’s a risk we wouldn’t have,” says Allen.

The Brindley experiment

That decision proves again that, in scientific discovery, timing can be critical. Just as the reports of NO’s role in penile erection spurred the decision to pursue UK-92,480’s unusual side effects, events in the 1980s helped set the stage for the development of an oral erectile dysfunction drug. “Twenty years ago, the prevailing view was that most erectile dysfunction was psychological. That inhibited physicians from taking an interest in the condition, and it inhibited patients from presenting. They didn’t want to be told it was all in their minds,” says Osterloh.

Organic causes of erectile dysfunction

In the early 1980s, researchers first developed injectable therapies called alpha-blockers, which work by blocking the interaction of norepinephrine with alpha receptors at the penile nerve endings. Norepinephrine’s role in the penis is to force the penile blood vessels to constrict, preventing an erection.

That an injection could produce an erection was initially met with skepticism, but a brash psychiatrist named Giles Brindley changed that with an unforgettable demonstration. “During a talk one year at the American Urological Association meeting, he stated that he had given himself a penile injection of phenoxybenzamine (an antihypertensive alpha-blocker) 20 minutes before the lecture, and he now had an erection. The audience said ‘show us,’ so he dropped his trousers. That demonstrated to a group of skeptical people that you really could take a drug to cause an erection,” Osterloh says.

Physicians and researchers suddenly got interested, and it was soon evident that several physical conditions – heart disease and diabetes, for example – could cause erectile dysfunction. Patients began to hope that their conditions could be treated. A drug for erectile dysfunction did become available: alprostadil (a PDE 1 inhibitor), which had to be either injected or inserted as an intraurethral pellet. However, apart from any consideration of alprostadil’s effectiveness, its means of delivery left much to be desired. The research that Brindley inspired continued, and by 1991, researchers were reporting that NO plays a role in penile erection – at just the right time for Allen and the Pfizer team to make the connection to UK-92,480’s unexpected side effect.

The erectile dysfunction trials

Pfizer was getting ready to drop efforts to develop the drug as an angina treatment, and the company faced a moment of truth. Should it drop the compound altogether, or should it pursue erectile dysfunction? It was hardly a simple decision. “The observation was made in healthy volunteers, but only those taking 3 doses a day for 10 days. None of the single-dose studies had shown erections, so it wasn’t clear that it would be of clinical use,” says Allen. Besides, only some of the healthy volunteers reported erections. How generally useful would the drug be?

Would it work in erectile dysfunction of organic cause? Moreover, how was Pfizer to conduct clinical trials for this disorder when diagnostic criteria, efficacy instruments, and regulatory guidelines were lacking? Still, there seemed to be a strong, if ill-defined, market. “Based on survey reports, we were thinking that about 1 in 20 men aged greater than 40 suffered from erectile dysfunction,” said Allen. Those estimates turned out to be conservative, perhaps because – given the dearth of acceptable treatments – many affected men were still not telling their doctors about their problems. “The estimates have increased since then,” said Allen. In the U.S. alone, there are an estimated 30 million affected men.

Pfizer had required time – from 1992 when the erection side effect surfaced until 1994 to assess the need and market for an erectile dysfunction medicine and to start new clinical trials. Now the company would learn whether, nine years from the project’s launch, the correct indication for UK-92,480 had been found. Its new trials tested the compound in men with erectile dysfunction. The results were immediately encouraging. Fears that the compound would take several days of multiple doses to work were quickly assuaged: In its May 1994 pilot study, 10 of 12 erectile dysfunction patients reported improved erections after just one dose (2 of 12 reported improvements with a placebo).

Pfizer took its pilot trial data to a urology conference. The company had no in-house expertise in urology, so presenting data at a medical conference was one of the ways Pfizer could confirm its judgment that the medicine was needed. The doctors’ reaction to the data was just what the company had hoped for: They were excited – the results obtained with this drug were far superior to those obtained with injectables. None of the physicians had imagined that a pill could be so effective. And as patients flocked to enroll in the trials, fears of a small market also subsided. “That made it clear that there were a lot of patients out there seeking help,” said Allen. UK-92,480 – Viagra – was beginning to look like a winner.

Viagra’s mechanism of action soon shed light on the differing results between healthy volunteers and men with erectile dysfunction. When sexually stimulated, men with erectile dysfunction do not produce enough NO in the penile nerves; therefore, cGMP levels do not become high enough to relax vascular muscles. So vessels do not dilate, blood does not flow into the erectile tissues, and the men cannot get erections. When Viagra is introduced, the low levels of NO produced during sexual stimulation are enough, because Viagra plugs the drain (i.e., PDE 5) and allows cGMP to build up and cause an erection. Normal men would not notice much difference: In the earlier trials, they had reported erections as a result of stimulation, but with less stimulation than normal.

Unlike injectable therapies, Viagra has no effect at all in the absence of sexual stimulation. cGMP is not produced until NO appears, and NO only arrives on the scene after sexual stimulation. This was good news because it would make the drug appealing to patients: They would not have erections when they did not want them. But it presented a challenge to the design of the clinical trials. How do you test a drug that requires sexual stimulation to be effective?

“There was no point in analyzing the effect unless there was sexual stimulation, and the quality of the sexual stimulation was going to be important, so obviously any assessment in a laboratory was bound to be artificial. The real test had to be in the home setting,” said Osterloh, who began designing the first series of trials in 1994. “How do you assess that? Anything that disrupts sexual stimulation will disrupt the efficacy as well. You can’t ask them to stop and take a picture.”

Osterloh turned to the idea of a diary, asking patients to document the effect of the erection – whether it helped or hindered other aspects of sex, such as sexual desire, orgasm, and the level of satisfaction of the partner. In some cases, he had the partner fill out a similar diary to back up the results. “Fortunately, the regulatory authorities bought into using these questionnaires as the main marker of efficacy,” says Osterloh.

The first major trials, from September 1994 to February 1995, were double-blind and involved 300 patients in the United Kingdom, France, Norway, and Sweden. Those trials returned results that were “almost too good to be true,” Osterloh says. At a 50-mg dose, 88% of patients using Viagra reported improved erections, while only 39% of those using a placebo did. Viagra patients’ erections improved. They had orgasms more easily. The orgasms were better, and they consistently reported an overall improvement in their sex lives. Even sexual desire improved, reaching the same levels as those of men who had participated as controls.

An open-label study with 225 patients followed. Clinical endpoints were the proportion of patients who said that their erections were improved and the proportion of patients wanting to continue treatment. Results: 87% voiced improvements in erection, and 90% wished to continue study treatment. The continuation statistic, even a number as high as 90%, fails to convey the way these men felt about Viagra. Consider, for instance, the small matter of the pills left over after clinical trials ended. Regulations require all pills distributed in trials to be accounted for, leftovers included. As patients were asked to turn in their unused pills, the Pfizer people were hearing things like “Oh, I flushed them down the toilet.” This was one medicine that would not be coming back.

When Pfizer informed trial participants that Viagra would not be available until after regulatory approval was obtained, many of them became despondent. They begged for more pills. Pfizer received poignant letters from many of these men expressing how they felt. Patients told, says Osterloh, “how devastating it had been to their self-esteem. We received letters from widowers who had met someone new but who felt they couldn’t contemplate marriage because of this problem. Others had had impotence break up the first marriage, and they didn’t want it to happen again. We’ve never had the level of patient response that we’ve had in this program.” Eventually, Pfizer decided to keep giving these men the Viagra they wanted, on grounds of compassion.

Viagra had finally arrived. It received FDA approval on March 27, 1998, and in its first quarter on the U.S. market, there were 2.9 million Viagra prescriptions, far beyond Pfizer’s predictions. In part, the availability of Viagra has driven its demand. Men with an impotence problem have read about it and realized that they are not alone in their suffering. It is not all in their heads, and there is an easy-to-take medicine that can help them. The drug that changed its indication twice is making Pfizer, and millions of impotent men around the world, very happy indeed.

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