Issue Date: January 15, 2007
ACS Award for Team Innovation
Sponsored by Corporation Associates
More and more during the past quarter- century, the emergence of highly resistant strains of Streptococcus pneumoniae, Enterococcus faecium, and Staphyloccus aureus has laid the groundwork for a medical crisis, especially among hospital patients. These bacteria cause pneumonia, bloodstream infections, and soft-tissue infections. But the teamwork of four former Upjohn Co. researchers who epitomize the definition of "collaborators" has led to "the first member of any entirely new class of antibacterial agents to reach the market in 35 years," according to Martin Mackay, senior vice president of Pfizer Global Research & Development.
The organic chemists who will share the award include Michael R. Barbachyn, Steven J. Brickner, and Douglas K. Hutchinson, the three coinventors of linezolid (Zyvox)-the first member of the oxazolidinone class of antibiotics to be approved for the treatment of serious gram-positive nosocomial (meaning originating or taking place in a hospital) infection. The fourth awardee is Peter R. Manninen, who is recognized for his identification of a breakthrough in the synthesis of optically active oxazolidinones.
Brickner, 52 , who has been a research fellow in antibacterials chemistry at Pfizer in Groton, Conn., since 2001, initiated the synthetic chemistry program leading to Zyvox as a spare-time project while working at Upjohn from 1982 to 1996. He says that when his lab was joined by Hutchinson's lab and then by Barbachyn's, they developed "a different operating model-one that came to engender a strong, effective team spirit with extensive sharing, not only of chemical intermediates but also ideas and strategies for prioritizing and prosecuting them as rapidly as possible." This approach led the team to select its first drug candidates, eperezolid and linezolid.
Barbachyn, 50, currently director of antibacterials chemistry at Pfizer in Ann Arbor, Mich., says that he "can't emphasize enough that this method of operating, something that we take for granted now, was truly an innovation back in the early 1990s."
Hutchinson, 51, is currently a research investigator with Abbott Laboratories. His scientific interests continue to lie in synthetic organic chemistry that is related to biologically active compounds, especially antiviral agents, oxazolidinone antibacterial agents, peptidomimetics, and organometallic chemistry. He says the team's approach that led to its focus on the piperazinyl oxazolidinones, "efforts which eventually segued into linezolid," is not universal in how things are done in the pharmaceutical industry. However, he says, "such an approach certainly allows everyone to have more fun with the chemistry and, perhaps ironically, makes a successful outcome for the project more likely. Certainly, trying to apply as many chemical resources to a project as possible to solve a clinical problem whose solution is never, ever obvious remains a motivating factor for me to this day."
"A second innovative approach instituted by our team," Brickner says, "was to prosecute our medicinal chemistry strategy based on obtaining, early on, safety information derived from monthlong toxicology studies and using this information to complement the normal correlation of structure with potency, efficacy, and pharmacokinetic properties.
"Having heard fragmentary information that DuPont—the original discoverer of the antibacterial oxazolidinones—had abandoned its oxazolidinone program (presumably because of toxicity), we went on to demonstrate the necessity of conducting these labor-intensive safety evaluations in order to identify those series with the best safety profiles. This represents arguably one of the first programs within the industry to successfully deliver to the market a first-in-class drug based on this then-uncommon strategy of running multiple, early preclinical toxicological evaluations to drive compound selection for development."
Barbachyn notes another "innovation that should be highlighted is the finding that incorporation of one or two strategically positioned fluorine atoms on the phenyl ring of our best oxazolidinones, including linezolid, confers advantageous properties to the oxazolidinone pharmacophore. In some cases, a potency advantage was realized; in others, there were observations of improved oral efficacy and pharmacokinetic performance. Perhaps most important was the finding that the monofluoro congeners usually exhibit improved water solubility, a critically important observation and innovation that enabled the realization of intravenously administered oxazolidinones, including linezolid."
Brickner, Barbachyn, and Hutchinson all point to the role played by Manninen, who was Brickner's laboratory associate, for his independent finding of a critical modification-that is, the use of a lithium base in the oxazolidinone cyclization. This new "Manninen reaction" provided an improved process that allowed the researchers "to synthesize oxazolidinones in very high optical purity and on a large scale," Brickner adds.
Manninen, 44, who is now a senior associate organic chemist with Eli Lilly & Co., says it was early in his career when he worked on the discovery of Zyvox, and he feels fortunate to have had the three other award winners as mentors: "For me, it is an honor to be included with them as a recipient of this award and very humbling at the same time, knowing that it takes far more than a few people to discover and develop a marketable drug to provide to patients in need. Drug discovery to help those who are suffering is the goal, but working through the science to accomplish that goal is a passion. I think every medicinal chemist out there has that passion or they wouldn't be doing drug discovery."
Speaking for the group, Brickner says: "With the knowledge that Zyvox has now been used for over 1 million patients, many of whom were very seriously ill, it is extremely gratifying to know that our collective work with very many other colleagues has delivered a lifesaving drug to those in need. Without the excellent scientific insights of our colleagues, particularly those in the disciplines of biology, drug metabolism, and toxicology, this project would never have progressed beyond its early stage as a breeder project."
The award address will be presented before the Division of Medicinal Chemistry.
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