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Zoloft, Pfizer's antidepressant drug, was discovered and developed more than 20 years ago when Pfizer was a much smaller company than it is today. Drug discovery and development, although regimented and centrally controlled, was handled differently than it is now. Marketing concerns were effectively kept out of the lab, and time constraints interfered less with freewheeling scientific inquiry, according to researchers on the Zoloft team at Pfizer, this year's recipients of the ACS Award for Team Innovation.
Team members and others familiar with their work agree that the drug and the team that discovered it evolved through a serendipitous process of scientific inquiry. The members, organic chemist Reinhard Sarges, 70; biochemist B. Kenneth Koe, 80; organic chemist Willard M. Welch, 61; animal behavioral scientist Albert Weissman, 72; and Pfizer's head of central nervous system drug research, Charles A. Harbert, 65; were recognized leaders in their fields of science. And each took an interest in the others' work in advancing a project that took shape as a quest for a selective serotonin reuptake inhibitor (SSRI) only in its later stages.
The invention of Zoloft (sertraline) began in the early 1970s, when Sarges synthesized a compound called tametraline, a norepinephrine reuptake inhibitor that was not developed further because of its propensity to cause stimulant side effects in rats. It was not forgotten, however. A second generation of compounds generated by Koe and Welch, in which chlorine substituents were added and the conformational chemistry was changed, led to racemic compounds characterized in vitro as SSRIs.
After Welch resolved the racemate into the pure enantiomers, testing via in vivo models by Weissman proved the cis (+) isomer to be particularly active as an SSRI antidepressant, and the team went on to develop sertraline hydrochloride into the highly efficacious SSRI drug we now know as Zoloft.
"We didn't start by looking for an antidepressant of this type," Weissman says. "We spent a lot of time on things that weren't obvious at the beginning." Many of the group's observations, he says, were "accidental."
Koe agrees. "This was not like your typical practice in which you are very goal-driven," he says. "Not until the end of the process did the group focus on any one drug."
According to Welch, the Zoloft team worked to some extent outside the mainstream at Pfizer. But the company's environment accommodated this kind of research. "It was different at that time in that we didn't have a formal project team," he says. But at Pfizer, he adds, a lack of formality did not get in the way of teamwork. "At Pfizer, I always felt that teams worked together."
"This team was one of veterans who researched and published productively," Weissman says.
Sheldon H. Preskorn, chair for the department of psychiatry and behavioral sciences at the University of Kansas and an adviser to Pfizer at the time that Zoloft was developed, attests to the innovative teamwork behind the drug's development. "Bench-type research drove the project forward," he says. "A number of people with unique perspectives forged the drug." The fact that the story of Zoloft prominently features basic science as opposed to clinical work is unique, he says.
Another adviser, Elias J. Corey of Harvard University's department of chemistry and chemical biology, agrees, noting that the team managed to pursue a course of open inquiry under unique pressure: Pfizer, at the time, was considering in-licensing an antidepression compound. Preskorn and Corey agree that the group did an effective job as champions of their project, succeeding finally in getting Pfizer to pursue Zoloft rather than the licensed-compound option.
Preskorn notes that the group's work, although innovative for its time, stands in contrast to the current state of drug discovery and development in a fundamental way. "Things now are more marketing-driven," he says. "In those days, people did things for scientific reasons. And they turned out innovative and novel drugs."
Perhaps it is the drug that speaks most about the team's innovation. Zoloft, introduced in 1992, was the first enantiomerically pure SSRI drug to hit the market. "It was a medication that was safe, well-tolerated, and easy to optimally dose," Preskorn says. Its safety and efficacy, when used in combination with other drugs, helped change the approach to treating clinical depression, he says. "It's the class act of the SSRI group."
The award address will be presented before the Division of Medicinal Chemistry.-Rick Mullin