title: Novel biaryl oxazolidinones: in vitro and in vivo activities with pharmacokinetics in an animal model.
abstract: RBx 1000075 and RBx 1000276, the new investigational oxazolidinones, have an extended spectrum of in vitro activity against Gram-positive pathogens and showed minimum inhibitory concentrations (MICs) lower than comparator drugs. MIC for 90% of the organisms (MIC(90)) values of RBx 1000075, RBx 1000276 and linezolid against the isolates tested were, respectively: methicillin-sensitive Staphylococcus aureus, 0.25, 1 and 4 microg/mL; methicillin-resistant S. aureus (MRSA), 0.5, 2 and 4 microg/mL; methicillin-sensitive Staphylococcus epidermidis, 0.25, 1 and 2 microg/mL; methicillin-resistant S. epidermidis, 0.5, 1 and 2 microg/mL; and enterococci, 0.25, 1 and 4 microg/mL. Against respiratory pathogens, MIC(90) values were: Streptococcus pneumoniae, 0.125, 0.5 and 2 microg/mL; Streptococcus pyogenes, 1, 0.5 and 2 microg/mL; and Moraxella catarrhalis, 0.5, 2 and 4 microg/mL. In vivo efficacies of RBx 1000075 and RBx 1000276 were evaluated in murine systemic infection against S. aureus (MRSA 562) and in a pulmonary infection model against S. pneumoniae ATCC 6303. In murine systemic infection, RBx 1000075 and RBx 1000276 showed efficacy against MRSA 562, exhibiting a 50% effective dose (ED(50)) of 6.25 and 9.92 mg/kg body weight for once-daily administration and 4.96 and 5.56 mg/kg body weight for twice-daily administration, respectively, whereas for linezolid the corresponding ED(50) values were 9.9 and 5.56 mg/kg body weight. In pulmonary infection with S. pneumoniae ATCC 6303, 50% survival was observed with RBx 1000075 at 50mg/kg once daily, whereas 60% survival was observed with RBx 1000276 at 50mg/kg thrice daily. The absolute oral bioavailabilities of RBx 1000075 and RBx 1000276 were 48% and 73%, with half-lives of 13.5 and 3.2h, respectively. RBx 1000075 and RBx 1000276 are promising investigational oxazolidinones against Gram-positive pathogens.
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India.
authors.forename: Tarani Kanta
authors.initials: TK
authors.lastname: Barman
authors.forename: Manisha
authors.initials: M
authors.lastname: Pandya
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.forename: Tripti
authors.initials: T
authors.lastname: Bhadauriya
authors.forename: Madhvi
authors.initials: M
authors.lastname: Rao
authors.forename: Seema
authors.initials: S
authors.lastname: Khan
authors.forename: Smita
authors.initials: S
authors.lastname: Singhal
authors.forename: Pragya
authors.initials: P
authors.lastname: Bhateja
authors.forename: Ruchi
authors.initials: R
authors.lastname: Sood
authors.forename: Sunita
authors.initials: S
authors.lastname: Malhotra
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.forename: Jyoti
authors.initials: J
authors.lastname: Paliwal
authors.forename: Pradip Kumar
authors.initials: PK
authors.lastname: Bhatnagar
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Upadhyay
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018410:Pneumonia, Bacterial / Q000188:drug therapy; D018805:Sepsis / Q000188:drug therapy; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D023303:Oxazolidinones