A new class. Linezolid (Zyvox), the first FDA-approved drug in the oxazolidinone class of synthetic antibiotics, has sparked combinatorial efforts to create even more effective antimicrobials that are based on the same nitrogen–oxygen heterocyclic five-membered ring structural moiety.

Mike Gordeev, director of chemistry at Versicor, Inc. (Fremont, CA), and collaborators at Pharmacia Corp. (Peapack, NJ) have explored new oxazolidinone compounds to improve on this prototype. He presented some of their early findings at the Drug Discovery Japan Conference in Tokyo in March.

The Versicor group started by creating a large library of structurally diverse oxazolidinones. Initial results were modest, however, with the antimicrobial activity of the first hits merely approaching the potency of linezolid. Subsequently, the chemists refocused on specific modifications around the oxazolidinone structure. For each targeted variation, they made several small libraries of new analogues on a solid phase and evaluated them for antimicrobial activity. The number of library members was about 100–500 in each structural class. “We believe in [an] integrated combichem–medchem approach, wherein relatively small SAR-guided libraries can generate quality leads,” said Gordeev.

He thinks that there is a trend toward smaller targeted libraries. “At this stage, it is hard to get people excited by sheer numbers of library components. Most companies are looking for compounds that fit the strict requirements of a product candidate,” he said.

Gordeev presented a synthetic approach in which an advanced pharmacophore reagent is made in solution and then tethered to a polymeric support to be used for solid-phase library synthesis. This methodology allows the scientists to avoid some difficult solid-phase chemistry. “We are being pragmatic,” said Gordeev.

The Versicor group constructed libraries in the amide, reverse amide, and sulfonamide C-group oxazolidinone series. Gordeev described in detail two solid-phase processes developed by Versicor scientists that accessed the key resin-bound pharmacophore intermediates. The first reaction worked via an aza-Wittig immobilization, and the second by a Curtius rearrangement. Noted Gordeev, “To my knowledge, these transformations have never been done on a solid phase before.” Versicor scientists identified several new motifs around the oxazolidinone structure that expand the structure–activity relationships of early experiments in the field. “This may allow for development of new compounds with improved properties,” Gordeev said. In fact, some of the novel oxazolidinones developed by his group have a significantly improved potency and spectrum compared with linezolid.