Beyond Viagra: other phosphodiesterase inhibitors are candidates for potential therapies

The same basic process used by the popular pharmaceutical Viagra may someday help people suffering from a variety of conditions, from allergies to diabetes. Viagra’s success has raised interest in the growing study of phosphodiesterase (PDE) inhibitors, says Joseph Beavo, Ph.D., a professor of pharmacology at the University of Washington School of Medicine.

Viagra works by inhibiting one specific type of enzyme called a cyclic GMP phosphodiesterase. "There is not just one, but many phosphodiesterases. Different PDEs are expressed in different tissues and in different parts of the cell, and have different physiological functions. The challenge has been for the drug companies to find agents that are selective for specific phosphodiesterases so that they can treat the disease without causing toxic side effects," Beavo says.

Beavo discussed PDEs and their inhibitors during the "Signal Transduction" panel at the American Association for the Advancement of Science annual meeting here today.

The different PDEs make up a large class of enzymes. Beavo and his colleagues discovered many of the 11 families that are recognized so far. These enzymes are found throughout the body, where they modulate many important functions. For example, they play a key role in many sensory processes including vision and smell. They may even play a role in learning and memory. On the one hand, this means that drugs regulating PDEs may someday provide a treatment for people with vision or memory problems. But at the same time, any researcher wanting to use PDE inhibitors to treat one specific part of the body must make sure that the therapy does not interfere with other PDEs – such as the ones involved in vision or memory.

Most PDE inhibitors currently available as medication affect PDEs in multiple organs, and so their use is often limited by their toxic side effects. Viagra, introduced in 1999, became a poster child for PDE research in part because of its selectivity.

"Viagra was the first really successful PDE inhibitor, both mechanistically and commercially," Beavo says. Viagra has generated more than $1 billion in sales. It is among the most widely prescribed drugs.

Viagra is a very selective drug. It acts on one specific PDE found in the penis. In the presence of nitric oxide, a signaling molecule released from the nerves in the penis, inhibition of this PDE helps cause an erection.

Here is why inhibition of the PDE has that effect: nitric oxide causes the production of a secondary signaling chemical, cyclic GMP, which leads to erection. During sexual stimulation, men with erectile dysfunction may have trouble producing enough cGMP. Normally, the PDE breaks down the cGMP into molecules that cannot cause erection. By inhibiting the breakdown of cGMP, Viagra leads to more cGMP. In other words, PDEs cause reductions in the needed chemical in the penis, and Viagra blocks the PDE to prevent this from happening. Viagra generally does not have side effects caused by inhibition of other PDEs.

"We use Viagra's mechanism of action as a beautiful example of drug and physiological selectivity when we talk to students," Beavo says. Researchers are now seeking other PDE inhibitors that will also act selectively, without toxic side effects throughout the body. Since many PDEs have been discovered only within the past year, the search is just beginning.

Beavo’s lab recently characterized PDE7 and PDE8, which can be induced in certain kinds of immune cells -- particularly T-cells. These two families of PDE do not break down cGMP; instead, they reduce cAMP, a similar signaling molecule, found in those immune cells. Since these PDEs appear to be very important for immune system activity, researchers are studying whether inhibitors of these enzymes might have an effect on anti-immune and hyper-inflammatory diseases such as rheumatoid arthritis and allergies. Other PDEs are thought to mediate other processes. PDE3 affects insulin secretion (with potential involvement in diabetes) and leptin signaling (with dietary and fat implications). Researchers at drug companies and other universities are examining how PDE inhibitors may be used to improve memory, treat chronic obstructive pulmonary disease and blood clotting disorders. In all of these examples, considerable work and testing will be needed before there are clinical benefits, Beavo said.