Viagra and the value of serendipity
Jackie Corbin, Ph.D., didn’t set out to develop a drug. He just wanted to do good science and understand how the body works.
He couldn’t have known at the outset of his career that his work would lay the foundation for the blockbuster drugs for erectile dysfunction: Viagra and related compounds.
It’s hard to pinpoint the first step down the road that led to Viagra, but Corbin, professor of Molecular Physiology & Biophysics at Vanderbilt, has forged ahead on this path since the 1960s.
“We never had any thoughts about developing any pills when we started our research,” says Corbin. “When my research first started, we were trying to figure out how cyclic nucleosides (cyclic AMP and cyclic GMP) worked in the body. That was a very basic physiological question.”
Cyclic GMP and cyclic AMP are second messengers, molecules that carry signals from the cell surface to proteins within the cell. Earl Sutherland, M.D., the late Nobel laureate and Vanderbilt professor, discovered cyclic AMP in the 1950s while studying the cellular action of hormones. Cyclic GMP was discovered later.
Sutherland’s work also suggested the existence of enzymes called phosphodiesterases, of PDEs, which degrade cyclic nucleotides.
In the early 1970s, scientists knew that cyclic AMP and cyclic GMP bind to and activate intracellular protein kinases, enzymes that regulate the activity of other cellular proteins. It was believed that these were the only cyclic nucleotide-binding proteins present in mammals.
In 1976, Corbin and his postdoctoral student, Tom Lincoln, Ph.D., identified a novel protein that bound to cyclic GMP. Lincoln and their colleagues Sharron Francis, Ph.D., currently research professor of Molecular Physiology & Biophysics, eventually purified and characterized the newly recognized protein, determining that it was a phosphodiesterase that degrades cyclic GMP. It was later named PDE5.
Around the same time, other groups shoed that increased intracellular cyclic GMP levels promote the relaxation of smooth muscle, while PDEs that degrade cyclic GMP counter this action. These findings suggested that blocking the enzymes could relax the musculature of blood vessels, and consequently lower blood pressure.
At that point, drug companies took interest.
“In the mid-’80s, drug companies would come to us and ask us for our enzyme and for our consultation to work to develop inhibitors to block (it),” Corbin says.
Pfizer Pharmaceutical developed and began testing one compound, but an interesting side effect shifted the company’s attention away from blood pressure.
“Sharron and I were at a meeting in the early ’90s, and had dinner with some of the Pfizer people,” Corbin recalls. “We knew they’d been working on these inhibitors, so we asked if they had any good ones. They said, ‘… we’ve got one where its effect on blood pressure is not that great, but some male patients have noticed it causes penile erection.’”
Pfizer began clinical trials of their compound, sildenafil (Viagra), on men with erectile dysfunction. The drug proved highly effective and had few side effects. Viagra hit the market in 1998 and soon became one of the best-selling drugs in history.
Today, Viagra and related PDE5 inhibitors tadalafil (Cialis) and vardenafil (Levitra) are some of the most financially successful drugs on the market. The drugs are now being studied in other conditions including pulmonary hypertension, Raynaud’s syndrome (a circulatory disorder), recovery from stroke, cystic fibrosis and as possible preventives for erectile dysfunction and heart disease.
“So we kind of accidentally entered the Viagra field by working on cyclic AMP and cyclic GMP, which just happened to be crucial mediators (of erectile dysfunction),” says Corbin, whose lab continues to investigate PDE5. “But we think that Viagra wouldn’t have been possible if we had not laid the groundwork and discovered the enzyme and the mechanism.
“Our work involved some logic, some prediction, some direction, but a lot of serendipity,” he continues. “I like to think that’s the way basic science ought to be.”
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