The Story of ZYVOX | Necessity, the Mother of ZYVOX
In reflecting on the discovery of ZYVOX, one may be reminded of the old adage, “necessity is the mother of invention.” For its discovery was born out of a determined effort to defeat the superbug MRSA and other pathogenic Gram-positive organisms, as well as provide relief for their vicious infections. It is no coincidence that this year’s winners began their work on ZYVOX two decades ago, just after multi-drug resistant infections first emerged as a public health concern.*
The 2007 Discoverers Award winners.
At an international scientific conference held in New York City in 1987, Dr. Steven Brickner, a synthetic organic chemist, listened to a scientist from Dupont describe an extraordinary new class of antibiotics, called oxazolidinones. Wholly synthetic and simple in structure, the two compounds described at the presentation possessed excellent pharmacokinetic properties. Additionally, their unique mechanism of action inhibited Gram-positive bacteria associated with serious infections without demonstrating cross resistance with any known antibiotics; Dupont scientists also were unable to induce resistance in the laboratory.
Brickner was intrigued by the results. He brought to his work a commitment to science and antibiotic research formed by the crucible of personal experience. “When I was in the eighth grade, a serious strep infection turned into Rheumatic Fever, and for one year I was confined to bed,” Brickner said. “Needless to say, I had a lot of time on my hands – during that time I developed a strong interest in chemistry. I learned about it through self-study and soon aspired to become a research scientist.”
Brickner understood the potential of what Dupont had discovered – the antibacterial agents he heard described could be effective against MRSA and other serious bugs – plus the opportunity. Oxazolidinones were an exciting new class of antibiotics, and so far “only one company was trying to bring it to market,” Brickner recalled. “There’s always room for one more.”
Back in Kalamazoo, he set out to find novel oxazolidinone compounds that would be effective. Amazingly enough, this work was done largely on his own time. An Upjohn† policy, unique then as it is now, allowed research scientists to spend 10 % of their time exploring long shots.
"Physicians are getting an important new weapon in the growing battle against drug-resistant infections: the U.S. government approved a long awaited drug called ZYVOX…"
- Health & Medicine Week (2000)
Within months, Brickner and his lab team developed several compounds that were similar in activity to the Dupont compounds. Then they heard through the grapevine that DuPont had terminated their oxazolidinone research program out of frustration with their compounds’ toxicity.
This created a serious dilemma for the Upjohn team: Now they had to produce a compound that was safe. What followed, Brickner said, was “a pivotal point” in the ultimate discovery of ZYVOX, as well as an amazing stroke of luck.
A toxicologist at Upjohn named Dr. Richard Piper offered to run 30-day toxicology studies. Like Brickner, Piper would be working on his own time. With DuPont’s experience fresh in his mind and corporate managers looking over his shoulder, Brickner selected what he thought was his best oxazolidinone prospect, called U-82965.
Thirty days later, the results were in – the compound was (relatively) nontoxic!
Even though Dupont soon thereafter acquired a patent on this first lead compound, Brickner’s stroke of luck in 1989 bought him more time – a toxicity result would most likely have ended the project.
More important, he and his lab team had established that a structure toxicity relationship existed for these compounds. This crucial knowledge would help the oxazolidinone team eventually identify 20–25 separate subclasses of oxazolidinones, some of which were found to exhibit good antibacterial activity and encouraging safety profiles.
“Highly unusual” is how Brickner described this phase of the project. “I can’t emphasize enough how many compounds we identified and put through tox studies before any of them were deemed drug candidates.” Then, the Brickner lab made two more crucial findings: first, in an indoline called U-85112, the introduction of a nitrogen atom on the phenyl group, which gave compounds improved safety; and second, the incorporation of a favored side chain, which would later prove useful in the discovery of Upjohn’s first oxazolidinone candidate, eperezolid.
Out of the hundreds of synthesized analogs that possessed promising safety profiles, the team eventually focused on one series, a step which ultimately bore fruit. Ingeniously and fortuitously, the compound that would become known as ZYVOX (linezolid) was conceived.
The 2007 Discoverers Award winners.
At an international scientific conference held in New York City in 1987, Dr. Steven Brickner, a synthetic organic chemist, listened to a scientist from Dupont describe an extraordinary new class of antibiotics, called oxazolidinones. Wholly synthetic and simple in structure, the two compounds described at the presentation possessed excellent pharmacokinetic properties. Additionally, their unique mechanism of action inhibited Gram-positive bacteria associated with serious infections without demonstrating cross resistance with any known antibiotics; Dupont scientists also were unable to induce resistance in the laboratory.
Brickner was intrigued by the results. He brought to his work a commitment to science and antibiotic research formed by the crucible of personal experience. “When I was in the eighth grade, a serious strep infection turned into Rheumatic Fever, and for one year I was confined to bed,” Brickner said. “Needless to say, I had a lot of time on my hands – during that time I developed a strong interest in chemistry. I learned about it through self-study and soon aspired to become a research scientist.”
Brickner understood the potential of what Dupont had discovered – the antibacterial agents he heard described could be effective against MRSA and other serious bugs – plus the opportunity. Oxazolidinones were an exciting new class of antibiotics, and so far “only one company was trying to bring it to market,” Brickner recalled. “There’s always room for one more.”
Back in Kalamazoo, he set out to find novel oxazolidinone compounds that would be effective. Amazingly enough, this work was done largely on his own time. An Upjohn† policy, unique then as it is now, allowed research scientists to spend 10 % of their time exploring long shots.
"Physicians are getting an important new weapon in the growing battle against drug-resistant infections: the U.S. government approved a long awaited drug called ZYVOX…"
- Health & Medicine Week (2000)
Within months, Brickner and his lab team developed several compounds that were similar in activity to the Dupont compounds. Then they heard through the grapevine that DuPont had terminated their oxazolidinone research program out of frustration with their compounds’ toxicity.
This created a serious dilemma for the Upjohn team: Now they had to produce a compound that was safe. What followed, Brickner said, was “a pivotal point” in the ultimate discovery of ZYVOX, as well as an amazing stroke of luck.
A toxicologist at Upjohn named Dr. Richard Piper offered to run 30-day toxicology studies. Like Brickner, Piper would be working on his own time. With DuPont’s experience fresh in his mind and corporate managers looking over his shoulder, Brickner selected what he thought was his best oxazolidinone prospect, called U-82965.
Thirty days later, the results were in – the compound was (relatively) nontoxic!
Even though Dupont soon thereafter acquired a patent on this first lead compound, Brickner’s stroke of luck in 1989 bought him more time – a toxicity result would most likely have ended the project.
More important, he and his lab team had established that a structure toxicity relationship existed for these compounds. This crucial knowledge would help the oxazolidinone team eventually identify 20–25 separate subclasses of oxazolidinones, some of which were found to exhibit good antibacterial activity and encouraging safety profiles.
“Highly unusual” is how Brickner described this phase of the project. “I can’t emphasize enough how many compounds we identified and put through tox studies before any of them were deemed drug candidates.” Then, the Brickner lab made two more crucial findings: first, in an indoline called U-85112, the introduction of a nitrogen atom on the phenyl group, which gave compounds improved safety; and second, the incorporation of a favored side chain, which would later prove useful in the discovery of Upjohn’s first oxazolidinone candidate, eperezolid.
Out of the hundreds of synthesized analogs that possessed promising safety profiles, the team eventually focused on one series, a step which ultimately bore fruit. Ingeniously and fortuitously, the compound that would become known as ZYVOX (linezolid) was conceived.