With a range of expertise on campus, from traditional medicinal chemistry to biotechnology to computational modeling, Rensselaer researchers are addressing problems inherent in drug discovery and development.

By Jill U. Adams     Printer-friendly PDF version

As drug makers target increasingly complex, chronic illnesses, drug development becomes far more costly and time consuming. Meanwhile, in the search for new drugs, 99.9 percent of compounds tested fail. Accordingly, drug makers want to be able to predict more accurately and test more efficiently which compounds will produce the next blockbuster drug. Rensselaer faculty are working at the leading edge of drug discovery research, exploring new technologies and contributing new understanding to the fields of chemistry and pharmacology.

Researching and creating new drug therapies is a needle in a haystack problem, with two complications. First, the haystack has to be constructed; the molecules must be made before they can be tested. Second, the needle is not obvious; the molecular characteristics that distinguish potential therapeutic drugs from the pack are largely unknown.

With a range of expertise on campus, from traditional medicinal chemistry to biotechnology to computational modeling, Rensselaer researchers are addressing these problems inherent in drug discovery and development.

“The pharmaceutical companies all want to use new technologies so they could make their drugs faster and cheaper,” says Mark Wentland, professor of chemistry. “The problem is it’s a very costly exercise to get drugs into humans.”

Medicinal chemistry, foremost among traditional approaches to drug discovery and development, retains its value in a high-tech world, he says. Wentland, who previously worked at the pharmaceutical company Sterling Winthrop, straddles the boundary between basic and applied research. A medicinal chemist is “a person whose primary aim is to get a drug into the clinic,” he says. Wentland has deliberately chosen an area with an unmet therapeutic need, cocaine addiction.

Wentland’s starting point is an opiate drug called cyclazocine, which produces the desired pharmacological effect. Cocaine itself stimulates reward pathways in the brain by increasing the release of a neurotransmitter called dopamine. Cyclazocine dampens dopamine release by acting on two different types of cell surface receptors, “a double whammy,” says Wentland. However, cyclazocine’s short duration of action is a detriment to its therapeutic usefulness.

“Now, a medicinal chemist steps in and tries to fix the molecule with the right pharmacological properties,” says Wentland describing his approach. Because of a phenolic OH group in its structure, cyclazocine is metabolized very quickly to inactive components. “We tried to find a mimic for the phenolic OH—a bioisostere—that’s got similar pharmacology, but ameliorates the problem.”

In other words, Wentland wanted to make a drug that was more resistant to metabolism. “If you look at the textbook of medicinal chemistry—generically speaking—there are many of these ‘bioisosteric’ replacements for different groups. But they don’t always work. And what we found was not in the textbooks.”

His group has successfully synthesized a cyclazocine analog with a carboxamide group in place of the phenolic OH and, in collaboration with scientists at the University of Rochester, Harvard University, and the University of Minnesota, has shown similar biological activity with an extended duration of action.

Wentland says this work has “opened up a huge medicinal chemistry effort,” and with funding from the National Institutes of Health, he is studying the structure-activity relationships of this substitution on other opiate drugs as well.