The Story of ZYVOX | Pioneers of Collaborative Research
A new medicine has been called many things, but rarely a poster drug, one can imagine. But that’s exactly what the Harvard Business Review did last year, when it called ZYVOX “the poster drug … for a culture characterized by cross-functional collaboration and speedy execution. Through dialogue, the group created a product that neither the scientists, clinicians, nor marketers acting by themselves could have envisioned or executed.” 4
Integral to that pioneering endeavor were this year’s other winners, Dr. Douglas Hutchinson, whose lab teamed up with Brickner in 1990, and Dr. Michael Barbachyn, whose lab made its entrance a year later. Together, their three labs became the Oxazolidinone Working Group, which was led by Brickner and included a total of nine chemists.
"An important new weapon in the fight against antibiotic-resistant germs."
- The New York Times (2000)
Their primary mission was to develop a vancomycin equivalent that not only had a different mechanism of action, but also could be taken orally. No oral therapy for MRSA-caused infections or other multi-resistant strains existed, complicating treatment, lengthening hospital stays and increasing risks of re-infection and secondary infections – all of which cost lives and money. As the saying goes, hospitals are no place for sick people.
For Douglas Hutchinson, it can be said with some irony that pharmaceutical research was in his blood.
“My great-grandmother was a strict Christian Scientist and did not believe in medicine at all,” Hutchinson said. “While my grandmother felt the same way, she happened to marry an electrical engineer who had faith in science. She and my grandfather got into quite a row about whether my father would be vaccinated against diphtheria.”
“My grandfather had lost several family members, including a brother, to diphtheria, and he was not going to let my father fall ill when a preventative technology existed.”
“You might say I witnessed the logic of medicine intervening to save members of my family,” Hutchinson explained. “That was a powerful revelation, having grown up around my great-grandmother. She’s probably rolling in her grave, knowing her great-grandson is trying to discover drugs.”
Hutchinson’s role in the discovery of linezolid actually involved a major contribution to the discovery of its precursor, eperezolid. The Hutchinson laboratory’s initial focus was on exploring ways to make structure activity relationship refinements, eventually settling on a piperazine ring. From research on AIDS medicines, Hutchinson was aware of piperazine’s solubility, making it a good candidate for an oral therapy. It was also generally available, so that synthesis and ultimate manufacture was considerably easier.
While his was the third lab in, Michael Barbachyn’s role was no less crucial.
A high school teacher first sparked Barbachyn’s interest in chemistry, and an NSF undergraduate project led him to an interest in pursuing a graduate degree in chemistry and eventually into pharmaceutical research. But what drew him to antibiotic research specifically was its iterative process, which turns scientists into sleuths determined to outfox resistance.
“Bacteria are always developing resistance mechanisms,” Barbachyn said. “It is the constant reinventing, redesigning and readapting of antibacterial agents to address these mechanisms that really intrigues me.”
“Ironically, synthetic organic chemistry is often less science than art. There may be a dozen ways to synthetically make a molecule – that’s where art comes into it. It’s the abstract nature of antibiotic research that was the attraction.”
His most important contribution to the discovery of linezolid, Barbachyn and others agree, was his “realizing the potency, solubility and pharmacokinetic benefits” of incorporating one or two strategically positioned fluorine substituents on the oxazolidinone’s phenyl ring. Fluorination of the phenyl ring is a common structural feature of both eperezolid and linezolid.
In late 1992, the three scientists and their lab teams got together in a room, leaving their egos at the door, and set out to select the compound series with the most promise of becoming a drug candidate. They chose the piperazinyl oxazolidinone series.
“Selected piperazine derivatives exhibited excellent in vitro and in vivo activity while also maintaining an acceptable safety profile, good water solubility, and excellent pharmacokinetic parameters,” Barbachyn and two other colleagues wrote in 2001. “As a bonus the piperazine analogs were also the easiest compounds to synthesize. Because of these and other characteristics the piperazine series became the principal focus of the ongoing chemistry effort.” 5
"It is a major advance to have this option."
- Dr. George Eliopolous, Beth Israel Medical Center, Boston
Ultimately, this series led to the first Upjohn clinical oxazolidinone, eperezolid.
Hutchinson and his team created a piperazine intermediate that had enormous versatility, creating more chances for the scientists to discover compounds with even more activity, less toxicity and better pharmacokinetic properties.
“There were just a lot of things you could do with the piperazine series,” Hutchinson said. “I guess my process research background came through. I wanted to use some relatively straightforward chemistry and we were ultimately successful. I think that was the most important part of my contribution.”
In a brainstorming session with Brickner and Hutchinson in April 1993, Barbachyn persuaded his colleagues to consider replacing the usual piperazine moiety (found in eperezolid) with a morpholine or thiomorpholine residue. Subsequent testing of these prepared analogs, which included linezolid, confirmed that some of these compounds exhibited activity, solubility, and especially pharmacokinetic performance characteristics meeting many of the team’s criteria. This breakthrough eventually led the team to select the morpholine derivative now known as linezolid for further development. Remarkably, linezolid was synthesized just two days after eperezolid. Two days!
Integral to that pioneering endeavor were this year’s other winners, Dr. Douglas Hutchinson, whose lab teamed up with Brickner in 1990, and Dr. Michael Barbachyn, whose lab made its entrance a year later. Together, their three labs became the Oxazolidinone Working Group, which was led by Brickner and included a total of nine chemists.
"An important new weapon in the fight against antibiotic-resistant germs."
- The New York Times (2000)
Their primary mission was to develop a vancomycin equivalent that not only had a different mechanism of action, but also could be taken orally. No oral therapy for MRSA-caused infections or other multi-resistant strains existed, complicating treatment, lengthening hospital stays and increasing risks of re-infection and secondary infections – all of which cost lives and money. As the saying goes, hospitals are no place for sick people.
For Douglas Hutchinson, it can be said with some irony that pharmaceutical research was in his blood.
“My great-grandmother was a strict Christian Scientist and did not believe in medicine at all,” Hutchinson said. “While my grandmother felt the same way, she happened to marry an electrical engineer who had faith in science. She and my grandfather got into quite a row about whether my father would be vaccinated against diphtheria.”
“My grandfather had lost several family members, including a brother, to diphtheria, and he was not going to let my father fall ill when a preventative technology existed.”
“You might say I witnessed the logic of medicine intervening to save members of my family,” Hutchinson explained. “That was a powerful revelation, having grown up around my great-grandmother. She’s probably rolling in her grave, knowing her great-grandson is trying to discover drugs.”
Hutchinson’s role in the discovery of linezolid actually involved a major contribution to the discovery of its precursor, eperezolid. The Hutchinson laboratory’s initial focus was on exploring ways to make structure activity relationship refinements, eventually settling on a piperazine ring. From research on AIDS medicines, Hutchinson was aware of piperazine’s solubility, making it a good candidate for an oral therapy. It was also generally available, so that synthesis and ultimate manufacture was considerably easier.
While his was the third lab in, Michael Barbachyn’s role was no less crucial.
A high school teacher first sparked Barbachyn’s interest in chemistry, and an NSF undergraduate project led him to an interest in pursuing a graduate degree in chemistry and eventually into pharmaceutical research. But what drew him to antibiotic research specifically was its iterative process, which turns scientists into sleuths determined to outfox resistance.
“Bacteria are always developing resistance mechanisms,” Barbachyn said. “It is the constant reinventing, redesigning and readapting of antibacterial agents to address these mechanisms that really intrigues me.”
“Ironically, synthetic organic chemistry is often less science than art. There may be a dozen ways to synthetically make a molecule – that’s where art comes into it. It’s the abstract nature of antibiotic research that was the attraction.”
His most important contribution to the discovery of linezolid, Barbachyn and others agree, was his “realizing the potency, solubility and pharmacokinetic benefits” of incorporating one or two strategically positioned fluorine substituents on the oxazolidinone’s phenyl ring. Fluorination of the phenyl ring is a common structural feature of both eperezolid and linezolid.
In late 1992, the three scientists and their lab teams got together in a room, leaving their egos at the door, and set out to select the compound series with the most promise of becoming a drug candidate. They chose the piperazinyl oxazolidinone series.
“Selected piperazine derivatives exhibited excellent in vitro and in vivo activity while also maintaining an acceptable safety profile, good water solubility, and excellent pharmacokinetic parameters,” Barbachyn and two other colleagues wrote in 2001. “As a bonus the piperazine analogs were also the easiest compounds to synthesize. Because of these and other characteristics the piperazine series became the principal focus of the ongoing chemistry effort.” 5
"It is a major advance to have this option."
- Dr. George Eliopolous, Beth Israel Medical Center, Boston
Ultimately, this series led to the first Upjohn clinical oxazolidinone, eperezolid.
Hutchinson and his team created a piperazine intermediate that had enormous versatility, creating more chances for the scientists to discover compounds with even more activity, less toxicity and better pharmacokinetic properties.
“There were just a lot of things you could do with the piperazine series,” Hutchinson said. “I guess my process research background came through. I wanted to use some relatively straightforward chemistry and we were ultimately successful. I think that was the most important part of my contribution.”
In a brainstorming session with Brickner and Hutchinson in April 1993, Barbachyn persuaded his colleagues to consider replacing the usual piperazine moiety (found in eperezolid) with a morpholine or thiomorpholine residue. Subsequent testing of these prepared analogs, which included linezolid, confirmed that some of these compounds exhibited activity, solubility, and especially pharmacokinetic performance characteristics meeting many of the team’s criteria. This breakthrough eventually led the team to select the morpholine derivative now known as linezolid for further development. Remarkably, linezolid was synthesized just two days after eperezolid. Two days!