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ACS Award For Creative Invention

by Susan J. Ainsworth
January 26, 2015 | A version of this story appeared in Volume 93, Issue 4

Credit: Illertissen Press
Photo of Coe.
Credit: Illertissen Press

Sponsored by ACS Corporation Associates

When Jotham W. Coe looks back on the research that would lead to the smoking-cessation drug varenicline, now marketed as Chantix, he recalls that “chemistry was at the heart of my effort, but the more we worked on this, the more its relevance grew for me.

“I am an ex-smoker and have seen smoking take multiple family members, including my grandparents and my father,” adds Coe, 56, who is a research fellow at Pfizer Worldwide Research & Development. “Seeing our varenicline work help millions put smoking behind them gives me hope that we have spared them and their families from suffering through painful, often life-ending disease.”

Spurred by his desire to help others, “Coe was a major contributor to the conception of analogs, design of enabling synthetic technology, and development of structure-activity relationships that made the varenicline program successful,” says Rod MacKenzie, group senior vice president, head of PharmaTherapeutics R&D, and director of Groton Laboratories at Pfizer.

Coe and his team recognized that smokers attempting to quit are challenged by their physical addiction to nicotine. Nicotine’s addictive properties result from its action on neuronal nicotinic acetylcholine receptors (nAChRs) in the brain, MacKenzie notes. Nicotine’s activation of a particularly abundant nAChR subtype called α4β2 increases the release of dopamine, a neurotransmitter that is associated with most drugs of abuse. Smokers quickly become dependent on the bursts of dopamine that accompany each drag on a cigarette.

Varenicline is effective because it partially activates α4β2 to provide moderate and sustained release of dopamine, “easing the cravings experienced by many smokers who try cold-turkey methods,” MacKenzie explains. At the same time, varenicline binds tightly to the α4β2 receptor, blocking nicotine from binding so smokers get no satisfaction from lighting up.

In solving the synthetic puzzles behind varenicline, “Jotham had to overcome so many obstacles that his persistence was as noteworthy as his great creativity and scientific ability,” says Elias J. Corey, Harvard University professor and Nobel Laureate in chemistry, who was an adviser on the Pfizer project. “The research itself was brilliantly executed, sophisticated synthetic chemistry performed by an extraordinarily talented and determined scientist,” he adds.

Justin Du Bois, associate professor of chemistry at Stanford University, concurs. “The invention of varenicline is testament to Coe’s creativity as a problem solver and his terrific insight into medicinal chemistry,” he says. “The complicated biochemistry and pharmacology of nAChRs and the extreme challenges in drug design posed by this protein family make the discovery of Chantix one of the great success stories in pharmaceutical research in the past 20 years.”

Born in Cambridge, Mass., Coe earned an A.B. in chemistry at Harvard in 1981 and a Ph.D. in chemistry at Massachusetts Institute of Technology in 1988, just before joining Pfizer.

Although this ACS award goes to Coe, he feels it “recognizes the chemistry and research accomplishment of our team and our company.” He adds: “We were all driven by the objective to help people through the challenges of quitting and spare them smoking-related disease. The research behind it was tough, at times exhilarating, an uncharted path. Nothing could be more rewarding than to see it develop into a major treatment advance.”

Coe will present his award address before the Division of Organic Chemistry.


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