title: Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections.
abstract: Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.
authors.affiliation: Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Brickner
authors.forename: D K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: M R
authors.initials: MR
authors.lastname: Barbachyn
authors.forename: P R
authors.initials: PR
authors.lastname: Manninen
authors.forename: D A
authors.initials: DA
authors.lastname: Ulanowicz
authors.forename: S A
authors.initials: SA
authors.lastname: Garmon
authors.forename: K C
authors.initials: KC
authors.lastname: Grega
authors.forename: S K
authors.initials: SK
authors.lastname: Hendges
authors.forename: D S
authors.initials: DS
authors.lastname: Toops
authors.forename: C W
authors.initials: CW
authors.lastname: Ford
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D005260:Female; D000069349:Linezolid; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008826:Microbial Sensitivity Tests; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D023303:Oxazolidinones; D051381:Rats
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D010080:Oxazoles; D023303:Oxazolidinones; C098011:eperezolid; D000069349:Linezolid