Linezolid - History

History

The oxazolidinones have been known as monoamine oxidase inhibitors since the late 1950s. Their antimicrobial properties were discovered by researchers at E.I. duPont de Nemours in the 1970s. In 1978, DuPont patented a series of oxazolidinone derivatives as being effective in the treatment of bacterial and fungal plant diseases, and in 1984, another patent described their usefulness in treating bacterial infections in mammals. In 1987, DuPont scientists presented a detailed description of the oxazolidinones as a new class of antibiotics with a novel mechanism of action. Early compounds were found to produce liver toxicity, however, and development was discontinued.

Pharmacia & Upjohn (now part of Pfizer) started its own oxazolidinone research program in the 1990s. Studies of the compounds' structure–activity relationships led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity. Two compounds were considered drug candidates: eperezolid (codenamed PNU-100592) and linezolid (PNU-100766). In the preclinical stages of development, they were similar in safety and antibacterial activity, so they were taken to Phase I clinical trials to identify any difference in pharmacokinetics. Linezolid was found to have a pharmacokinetic advantage—requiring only twice-daily dosage, while eperezolid needed to be given three times a day to achieve similar exposure—and therefore proceeded to further trials. The U.S. Food and Drug Administration (FDA) approved linezolid on April 18, 2000. Approval followed in Brazil (June 2000), the United Kingdom (January 2001), Japan and Canada (April 2001), Europe (throughout 2001), and other countries in Latin America and Asia.

As of 2009, linezolid is the only oxazolidinone antibiotic available. Other members of this class have entered development, such as posizolid (AZD2563), ranbezolid (RBx 7644), torezolid (TR-701), and radezolid (RX-1741).